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Goyal S, Tibrewal S, Ratna R, Vanita V. Genetic and environmental factors contributing to anophthalmia and microphthalmia: Current understanding and future directions. World J Clin Pediatr 2025; 14:101982. [DOI: 10.5409/wjcp.v14.i2.101982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 02/19/2025] [Accepted: 02/25/2025] [Indexed: 03/18/2025] Open
Abstract
Anophthalmia is defined as a complete absence of one eye or both the eyes, while microphthalmia represents the presence of a small eye within the orbit. The estimated birth prevalence for anophthalmia is approximately 3 per 100000 live births, and for microphthalmia, it is around 14 per 100000 live births. However, combined evidence suggests that the prevalence of these malformations could be as high as 30 per 100000 individuals. Microphthalmia is reported to occur in 3.2% to 11.2% of blind children. Anophthalmia and microphthalmia (A/M) are part of a phenotypic spectrum alongside ocular coloboma, hypothesized to share a common genetic basis. Both A/M can occur in isolation or as part of a syndrome. Their complex etiology involves chromosomal aberrations, monogenic inheritance pattern, and the contribution of environmental factors such as gestational-acquired infections, maternal vitamin A deficiency (VAD), exposure to X-rays, solvent misuse, and thalidomide exposure. A/M exhibit significant clinical and genetic heterogeneity with over 90 genes identified so far. Familial cases of A/M have a complex genetic basis, including all Mendelian modes of inheritance, i.e., autosomal dominant, recessive, and X-linked. Most cases arise sporadically due to de novo mutations. Examining gene expression during eye development and the effects of various environmental variables will help us better understand the phenotypic heterogeneity found in A/M, leading to more effective diagnosis and management strategies. The present review focuses on key genetic factors, developmental abnormalities, and environmental modifiers linked with A/M. It also emphasizes at potential research areas including multiomic methods and disease modeling with induced pluripotent stem cell technologies, which aim to create innovative treatment options.
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Affiliation(s)
- Shiwali Goyal
- Department of Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Rockville, MD 20852, United States
| | - Shailja Tibrewal
- Department of Pediatric Ophthalmology, Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Ria Ratna
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Vanita Vanita
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
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2
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Teng M, Guo J, Xu X, Ci X, Mo Y, Kohen Y, Ni Z, Chen S, Guo WY, Bakht M, Ku S, Sigouros M, Luo W, Macarios CM, Xia Z, Chen M, Ul Haq S, Yang W, Berlin A, van der Kwast T, Ellis L, Zoubeidi A, Zheng G, Ming J, Wang Y, Cui H, Lok BH, Raught B, Beltran H, Qin J, He HH. Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation. Cancer Cell 2025; 43:891-904.e10. [PMID: 40250444 DOI: 10.1016/j.ccell.2025.03.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 01/31/2025] [Accepted: 03/21/2025] [Indexed: 04/20/2025]
Abstract
Circular RNA (circRNA) is a class of noncoding RNA with regulatory potentials. Its role in the transdifferentiation of prostate and lung adenocarcinoma into neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC) remains unexplored. Here, we identified circRMST as an exceptionally abundant circRNA predominantly expressed in NEPC and SCLC, with strong conservation between humans and mice. Functional studies using shRNA, siRNA, CRISPR-Cas13, and Cas9 consistently demonstrate that circRMST is essential for tumor growth and the expression of ASCL1, a master regulator of neuroendocrine fate. Genetic knockout of Rmst in NEPC genetic engineered mouse models prevents neuroendocrine transdifferentiation, maintaining tumors in an adenocarcinoma state. Mechanistically, circRMST physically interacts with lineage transcription factors NKX2-1 and SOX2. Loss of circRMST induces NKX2-1 protein degradation through autophagy-lysosomal pathway and alters the genomic binding of SOX2, collectively leading to the loss of ASCL1 transcription.
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Affiliation(s)
- Mona Teng
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Jiacheng Guo
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Xin Xu
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Xinpei Ci
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Yulin Mo
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Yakup Kohen
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Zuyao Ni
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Sujun Chen
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Wang Yuan Guo
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Martin Bakht
- Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | - Shengyu Ku
- Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
| | - Michael Sigouros
- Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Wenqin Luo
- Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | | | - Ziting Xia
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada
| | - Moliang Chen
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Sami Ul Haq
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Wen Yang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Alejandro Berlin
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Theo van der Kwast
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Leigh Ellis
- Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA
| | - Amina Zoubeidi
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Gang Zheng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Jie Ming
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuzhuo Wang
- Vancouver Prostate Centre, Vancouver, BC, Canada; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Haissi Cui
- Department of Chemistry, University of Toronto, Toronto, ON, Canada
| | - Benjamin H Lok
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Brian Raught
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Himisha Beltran
- Division of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
| | - Jun Qin
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
| | - Housheng Hansen He
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
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Li Y, Oser MG. A circular RNA in neuroendocrine carcinomas. Cancer Cell 2025; 43:812-814. [PMID: 40250442 DOI: 10.1016/j.ccell.2025.03.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 03/25/2025] [Accepted: 03/25/2025] [Indexed: 04/20/2025]
Abstract
In this issue of Cancer Cell, Teng et al. discover that small cell lung cancer and neuroendocrine prostate cancer highly express a circular RNA known as circRMST. They show that circRMST is necessary for these neuroendocrine cancers to promote their ASCL1-positive neuroendocrine phenotype through binding lineage transcription factors that promote ASCL1 expression.
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Affiliation(s)
- Yixiang Li
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Matthew G Oser
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
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Tani H. Biomolecules Interacting with Long Noncoding RNAs. BIOLOGY 2025; 14:442. [PMID: 40282307 PMCID: PMC12025117 DOI: 10.3390/biology14040442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Revised: 04/18/2025] [Accepted: 04/18/2025] [Indexed: 04/29/2025]
Abstract
This review explores the complex interactions between long noncoding RNAs (lncRNAs) and other biomolecules, highlighting their pivotal roles in gene regulation and cellular function. LncRNAs, defined as RNA transcripts exceeding 200 nucleotides without encoding proteins, are involved in diverse biological processes, from embryogenesis to pathogenesis. They interact with DNA through mechanisms like triplex structure formation, influencing chromatin organization and gene expression. LncRNAs also modulate RNA-mediated processes, including mRNA stability, translational control, and splicing regulation. Their versatility stems from their forming of complex structures that enable interactions with various biomolecules. This review synthesizes current knowledge on lncRNA functions, discusses emerging roles in development and disease, and evaluates potential applications in diagnostics and therapeutics. By examining lncRNA interactions, it provides insights into the intricate regulatory networks governing cellular processes, underscoring the importance of lncRNAs in molecular biology. Unlike the majority of previous reviews that primarily focused on individual aspects of lncRNA biology, this comprehensive review uniquely integrates structural, functional, and mechanistic perspectives on lncRNA interactions across diverse biomolecules. Additionally, this review critically evaluates cutting-edge methodologies for studying lncRNA interactions, bridges fundamental molecular mechanisms with potential clinical applications, and highlights their potential.
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Affiliation(s)
- Hidenori Tani
- Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano, Totsuka, Yokohama 245-0066, Japan
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Duot M, Coomson SY, Shrestha SK, Nagulla MVMK, Audic Y, Barve RA, Huang H, Gautier-Courteille C, Paillard L, Lachke SA. Transcriptome Meta-Analysis Uncovers Cell-Specific Regulatory Relationships in Embryonic, Juvenile, Adult, and Aged Mouse Lens Epithelium and Fibers. Invest Ophthalmol Vis Sci 2025; 66:42. [PMID: 40238114 PMCID: PMC12011134 DOI: 10.1167/iovs.66.4.42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 03/21/2025] [Indexed: 04/18/2025] Open
Abstract
Purpose The lens transcriptome has been examined using microarrays and RNA-sequencing (RNA-seq). These omics data are the basis of the bioinformatics web-resource iSyTE that has identified new genes involved in lens development and cataract. The lens predominantly contains epithelial and fiber cells, and yet, presently, iSyTE is based on whole lens data. To gain cell-specific regulatory insights, we meta-analyzed isolated epithelium and fiber transcriptomes from embryonic/postnatal, adult and aged lenses. Methods Mouse lens epithelium and fiber transcriptome public datasets at embryonic (E) and postnatal (P) stages E12.5, E14.5, E16.5, E18.5, P0.5, P0, P5, P13, and age one month, three months, six months, and two years were analyzed. Microarray or RNA-seq data were analyzed by appropriate methods and compared to other resources (e.g., Cat-Map, CompBio). Results Across all RNA-seq datasets examined, 2466 genes are differentially expressed between epithelium and fibers, of which 106 are cataract-linked. Gene ontology enrichment validates epithelial and fiber expression, corroborating the meta-analysis. Whole embryonic-body-in silico subtraction and other analyses identify several new high-priority epithelial- and/or fiber-enriched genes (e.g., Casz1, Ell2). Furthermore, new insights into cell-specific regulatory processes at distinct stages are identified (e.g., ribonucleoprotein regulation in E12.5 epithelium). Finally, this data is made accessible at iSyTE (https://research.bioinformatics.udel.edu/iSyTE/). Conclusions This spatiotemporal transcriptome meta-analysis comprehensively informs on epithelium- and fiber-specific regulatory processes in developing, adult and aged lenses. Notably, it includes the first description of an embryonic stage (i.e., E12.5) representing early primary fiber differentiation, thus informing on the initial transcriptome changes as lens cell-types are readily distinguishable.
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Affiliation(s)
- Matthieu Duot
- Department of Biological Sciences, University of Delaware, Newark, Delaware, United States
- Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, Rennes, France
| | - Sarah Y. Coomson
- Department of Biological Sciences, University of Delaware, Newark, Delaware, United States
| | - Sanjaya K. Shrestha
- Department of Biological Sciences, University of Delaware, Newark, Delaware, United States
| | | | - Yann Audic
- Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, Rennes, France
| | - Ruteja A. Barve
- Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States
| | - Hongzhan Huang
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, Delaware, United States
| | - Carole Gautier-Courteille
- Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, Rennes, France
| | - Luc Paillard
- Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes) - UMR 6290, Rennes, France
| | - Salil A. Lachke
- Department of Biological Sciences, University of Delaware, Newark, Delaware, United States
- Center for Bioinformatics and Computational Biology, University of Delaware, Newark, Delaware, United States
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Tani H. RMST: a long noncoding RNA involved in cancer and disease. J Biochem 2025; 177:73-78. [PMID: 39673327 DOI: 10.1093/jb/mvae083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/01/2024] [Accepted: 11/28/2024] [Indexed: 12/16/2024] Open
Abstract
Long non-coding RNA rhabdomyosarcoma 2-associated transcript (RMST) is a crucial regulator in various biological processes, particularly in neurogenesis and cancer progression. This review summarizes current knowledge on structure, expression patterns and functional roles across different organs and diseases of RMST. RMST exhibits tissue-specific expression, notably in brain tissues and vascular endothelial cells, and plays a significant role in neuronal differentiation through interaction with SRY-box 2. In cancer, RMST predominantly functions as a tumour suppressor, with context-dependent roles observed across different cancer types. RMST is also implicated in neurological disorders, cardiovascular diseases and Hirschsprung's disease. Mechanistically, RMST acts as a competing endogenous RNA and a transcriptional regulator, interacting with various microRNAs and proteins to modulate gene expression. The potential of RMST as a biomarker and therapeutic target is increasingly recognized, particularly in atherosclerosis and cancer. While current findings are promising, further research is needed to fully elucidate the functions and translate these insights into clinical applications of RMST. This review underscores the significance of RMST in cellular processes and disease pathogenesis, highlighting its potential as a novel target for diagnostic and therapeutic interventions.
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Affiliation(s)
- Hidenori Tani
- Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano, Totsuka, Yokohama 245-0066, Japan
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7
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Argoetti A, Shalev D, Polyak G, Shima N, Biran H, Lahav T, Hashimshony T, Mandel-Gutfreund Y. lncRNA NORAD modulates STAT3/STAT1 balance and innate immune responses in human cells via interaction with STAT3. Nat Commun 2025; 16:571. [PMID: 39794357 PMCID: PMC11723954 DOI: 10.1038/s41467-025-55822-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 12/30/2024] [Indexed: 01/13/2025] Open
Abstract
Long non-coding RNAs (lncRNAs) are pivotal regulators of cellular processes. Here we reveal an interaction between the lncRNA NORAD, noted for its role in DNA stability, and the immune related transcription factor STAT3 in embryonic and differentiated human cells. Results from NORAD knockdown experiments implicate NORAD in facilitating STAT3 nuclear localization and suppressing antiviral gene activation. In NORAD-deficient cells, STAT3 remains cytoplasmic, allowing STAT1 to enhance antiviral activity. Analysis of RNA expression data from in vitro experiments and clinical samples demonstrates reduced NORAD upon viral infection. Additionally, evolutionary conservation analysis suggests that this regulatory function of NORAD is restricted to humans, potentially owing to the introduction of an Alu element in hominoids. Our findings thus suggest that NORAD functions as a modulator of STAT3-mediated immune suppression, adding to the understanding of lncRNAs in immune regulation and evolutionary adaptation in host defense mechanisms.
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Affiliation(s)
- Amir Argoetti
- Technion-Israel Institute of Technology, Faculty of Biology, Emerson building, Haifa, Israel
| | - Dor Shalev
- Technion-Israel Institute of Technology, Faculty of Biology, Emerson building, Haifa, Israel
| | - Galia Polyak
- Technion-Israel Institute of Technology, Faculty of Biology, Emerson building, Haifa, Israel
| | - Noa Shima
- Technion-Israel Institute of Technology, Faculty of Biology, Emerson building, Haifa, Israel
| | - Hadas Biran
- Technion-Israel Institute of Technology, Faculty of Computer Science, Taub building, Haifa, Israel
| | - Tamar Lahav
- Technion-Israel Institute of Technology, Faculty of Biology, Emerson building, Haifa, Israel
| | - Tamar Hashimshony
- Technion-Israel Institute of Technology, Faculty of Biology, Emerson building, Haifa, Israel
| | - Yael Mandel-Gutfreund
- Technion-Israel Institute of Technology, Faculty of Biology, Emerson building, Haifa, Israel.
- Technion-Israel Institute of Technology, Faculty of Computer Science, Taub building, Haifa, Israel.
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Li H, Jiang RY, Tang YJ, Ling C, Liu F, Xu JJ. Lnc-Pim1 Promotes Neurite Outgrowth and Regeneration of Neuron-Like Cells Following ACR-Induced Neuronal Injury. J Cell Biochem 2025; 126:e30659. [PMID: 39370596 DOI: 10.1002/jcb.30659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 08/24/2024] [Accepted: 09/11/2024] [Indexed: 10/08/2024]
Abstract
Decreased regenerative capacity of central nervous system neurons is the main cause for failure of damaged neuron regeneration and functional recovery. Long noncoding RNAs (lncRNAs) are abundant in mammalian transcriptomes, and many time- and tissue-specific lncRNAs are thought to be closely related to specific biological functions. The promoting effect of Pim-1 gene on neural differentiation and regeneration has been documented, but the effect and mechanism of its neighbor gene Lnc-Pim1 in regulating the response of central neurons to injury remain unclear. RT-PCR in this study demonstrated that the expression of Lnc-Pim1 was upregulated in acrylamide (ACR)-induced neuronal injury. FISH and nucleus-cytoplasmic assay demonstrated that Lnc-Pim1 was mainly expressed in the neuron cytoplasm, with a small amount in the nucleus. Western blot analysis proved that Lnc-Pim1 overexpression induced by the lentivirus vector could promote neurite outgrowth in Neuro-2a cells by activating the Erk1/2 signal pathway, and improve neurite regeneration of injured neurons by upregulating GAP-43 and β-Ⅲ tubulin protein expression. However, silencing Lnc-Pim1 expression by interfering RNA could effectively downregulate the GAP-43 and β-Ⅲ tubulin protein expression, and inhibit neurite growth of neurons. In addition, CHIRP-MS was performed to identify several potential targets of Lnc-Pim1 involved in the regulation of neurite regeneration of injured neurons. In conclusion, our study demonstrated that Lnc-Pim1 is a potential lnc-RNA, playing an important role in regulating central nerve regeneration.
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Affiliation(s)
- He Li
- Department of Anatomy, Second Military Medical University, Shanghai, P. R. China
| | - Ruo Yu Jiang
- Department of Anatomy, Second Military Medical University, Shanghai, P. R. China
| | - Ya Jie Tang
- Department of Anatomy, Second Military Medical University, Shanghai, P. R. China
| | - Cong Ling
- Department of Anatomy, Second Military Medical University, Shanghai, P. R. China
| | - Fang Liu
- Department of Anatomy, Second Military Medical University, Shanghai, P. R. China
| | - Jia Jun Xu
- Department of Anatomy, Second Military Medical University, Shanghai, P. R. China
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Cheng YF, Kempfle JS, Chiang H, Tani K, Wang Q, Chen SH, Lenz D, Chen WY, Wu W, Petrillo M, Edge ASB. Sox2 interacts with Atoh1 and Huwe1 loci to regulate Atoh1 transcription and stability during hair cell differentiation. PLoS Genet 2025; 21:e1011573. [PMID: 39883720 PMCID: PMC11813075 DOI: 10.1371/journal.pgen.1011573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 02/11/2025] [Accepted: 01/13/2025] [Indexed: 02/01/2025] Open
Abstract
Stem cell pluripotency gene Sox2 stimulates expression of proneural basic-helix-loop-helix transcription factor Atoh1. Sox2 is necessary for the development of cochlear hair cells and binds to the Atoh1 3' enhancer to stimulate Atoh1 expression. We show here that Sox2 deletion in late embryogenesis results in the formation of extra hair cells, in contrast to the absence of hair cell development obtained after Sox2 knockout early in gestation. Sox2 overexpression decreased the level of Atoh1 protein despite an increase in Atoh1 mRNA. Sox2 upregulated E3 ubiquitin ligase, Huwe1, by direct binding to the Huwe1 gene. By upregulating its cognate E3 ligase, Sox2 disrupts the positive feedback loop through which Atoh1 protein increases the expression of Atoh1. We conclude that Sox2 initiates expression, while also limiting continued activity of bHLH transcription factor, Atoh1, and this inhibition represents a new mechanism for regulating the activity of this powerful initiator of hair cell development.
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Affiliation(s)
- Yen-Fu Cheng
- Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, United States of America
- Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
- Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Judith S. Kempfle
- Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, United States of America
- Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
| | - Hao Chiang
- Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, United States of America
- Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
| | - Kohsuke Tani
- Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, United States of America
- Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
| | - Quan Wang
- Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, United States of America
- Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
| | - Sheng-Hong Chen
- Lab for Cell Dynamics, Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
- National Center for Theoretical Sciences, Physics Division, Taipei, Taiwan
| | - Danielle Lenz
- Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, United States of America
- Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
| | - Wei-Yi Chen
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wenjin Wu
- Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, United States of America
- Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
| | - Marco Petrillo
- Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, United States of America
- Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
| | - Albert S. B. Edge
- Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, United States of America
- Eaton-Peabody Laboratory, Massachusetts Eye and Ear, Boston, Massachusetts, United States of America
- Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, Massachusetts, United States of America
- Harvard Stem Cell Institute, Cambridge, Massachusetts, United States of America
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Li YY, Qian FC, Zhang GR, Li XC, Zhou LW, Yu ZM, Liu W, Wang QY, Li CQ. FunlncModel: integrating multi-omic features from upstream and downstream regulatory networks into a machine learning framework to identify functional lncRNAs. Brief Bioinform 2024; 26:bbae623. [PMID: 39602828 PMCID: PMC11601888 DOI: 10.1093/bib/bbae623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 10/26/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024] Open
Abstract
Accumulating evidence indicates that long noncoding RNAs (lncRNAs) play important roles in molecular and cellular biology. Although many algorithms have been developed to reveal their associations with complex diseases by using downstream targets, the upstream (epi)genetic regulatory information has not been sufficiently leveraged to predict the function of lncRNAs in various biological processes. Therefore, we present FunlncModel, a machine learning-based interpretable computational framework, which aims to screen out functional lncRNAs by integrating a large number of (epi)genetic features and functional genomic features from their upstream/downstream multi-omic regulatory networks. We adopted the random forest method to mine nearly 60 features in three categories from >2000 datasets across 11 data types, including transcription factors (TFs), histone modifications, typical enhancers, super-enhancers, methylation sites, and mRNAs. FunlncModel outperformed alternative methods for classification performance in human embryonic stem cell (hESC) (0.95 Area Under Curve (AUROC) and 0.97 Area Under the Precision-Recall Curve (AUPRC)). It could not only infer the most known lncRNAs that influence the states of stem cells, but also discover novel high-confidence functional lncRNAs. We extensively validated FunlncModel's efficacy by up to 27 cancer-related functional prediction tasks, which involved multiple cancer cell growth processes and cancer hallmarks. Meanwhile, we have also found that (epi)genetic regulatory features, such as TFs and histone modifications, serve as strong predictors for revealing the function of lncRNAs. Overall, FunlncModel is a strong and stable prediction model for identifying functional lncRNAs in specific cellular contexts. FunlncModel is available as a web server at https://bio.liclab.net/FunlncModel/.
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Affiliation(s)
- Yan-Yu Li
- The First Affiliated Hospital & National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- School of Computer, University of South China, Hengyang, Hunan, 421001, China
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Feng-Cui Qian
- The First Affiliated Hospital & National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- School of Computer, University of South China, Hengyang, Hunan, 421001, China
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Guo-Rui Zhang
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Xue-Cang Li
- School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, 163000, China
| | - Li-Wei Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Zheng-Min Yu
- School of Computer, University of South China, Hengyang, Hunan, 421001, China
| | - Wei Liu
- College of Science, Heilongjiang Institute of Technology, Harbin, Heilongjiang, 150000, China
| | - Qiu-Yu Wang
- The First Affiliated Hospital & National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- School of Computer, University of South China, Hengyang, Hunan, 421001, China
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Chun-Quan Li
- The First Affiliated Hospital & National Health Commission Key Laboratory of Birth Defect Research and Prevention, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
- Hunan Provincial Key Laboratory of Multi-omics and Artificial Intelligence of Cardiovascular Diseases, University of South China, Hengyang, Hunan, 421001, China
- Key Laboratory of Rare Pediatric Diseases, Ministry of Education, University of South China, Hengyang, Hunan, 421001, China
- School of Computer, University of South China, Hengyang, Hunan, 421001, China
- Institute of Biochemistry and Molecular Biology, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
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11
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Xu Q, Wang L, Song Q, Chen S, Du K, Teng X, Zou C. Distinct Hippocampal Expression Profiles of lncRNAs in Obese Type 2 Diabetes Mice Exhibiting Cognitive Impairment. Neuromolecular Med 2024; 26:42. [PMID: 39470862 DOI: 10.1007/s12017-024-08811-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 10/18/2024] [Indexed: 11/01/2024]
Abstract
Cognitive dysfunction has been accepted as a possible complication of type 2 diabetes (T2D), but few studies revealed the potential roles of Long non‑coding RNAs (lncRNAs) in cognitive dysfunction in T2D. The current research aims to demonstrate the specific expression patterns of lncRNA-mRNA in the hippocampi of T2D db/db mice exhibiting cognitive impairment. In this study, the results from behavioral tests showed that T2D db/db mice displayed short-term and spatial working memory deficits compared to db/m mice. Furthermore, western blot analysis demonstrated that compared with db/m mice, p-GSK3β (ser9) protein levels were markedly elevated in T2D db/db mice (P < 0.01). In addition, though not statistically significant, the ratio of p-Tau (Ser396) to Tau 46, α-Synuclein expression, and p-GSK3α (ser21) expression were also relatively higher in T2D db/db mice than in db/m mice. The microarray profiling revealed that 75 lncRNAs and 26 mRNAs were dysregulated in T2D db/db mice (> 2.0 fold change, P < 0.05). GO analysis demonstrated that the differentially expressed mRNAs participated in immune response, extracellular membrane-bounded organelle, and extracellular region. KEGG analysis revealed that the differentially expressed mRNAs were mainly involved in one carbon pool by folate, glyoxylate and dicarboxylate metabolism, autophagy, glycine, serine and threonine metabolism, and B cell receptor signaling pathway. A lncRNA‑mRNA coexpression network containing 71 lncRNAs and 26 mRNAs was built to investigate the interaction between lncRNA and mRNA. Collectively, these results revealed the differential hippocampal expression profiles of lncRNAs in T2D mice with cognitive dysfunction, and the findings from this study provide new clues for exploring the potential roles of lncRNAs in the pathogenesis of cognitive dysfunction in T2D.
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Affiliation(s)
- Qianqian Xu
- Key Laboratory of Longevity and Aging-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Lihui Wang
- Key Laboratory of Longevity and Aging-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Qiong Song
- Key Laboratory of Longevity and Aging-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Shuai Chen
- Key Laboratory of Longevity and Aging-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Kechen Du
- Key Laboratory of Longevity and Aging-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Xiahong Teng
- School of International Education, Guangxi Medical University, Nanning, 530021, Guangxi, China.
| | - Chunlin Zou
- Key Laboratory of Longevity and Aging-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China.
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed By the Province and Ministry, Guangxi Key Laboratory of Regenerative Medicine, Nanning, Guangxi, China.
- Department of Human Anatomy, Institute of Neuroscience and Guangxi Key Laboratory of Brain Science, School of Basic Medical Sciences, Guangxi Medical University, Nanning, Guangxi, China.
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12
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Schaefer T, Mittal N, Wang H, Ataman M, Candido S, Lötscher J, Velychko S, Tintignac L, Bock T, Börsch A, Baßler J, Rao TN, Zmajkovic J, Roffeis S, Löliger J, Jacob F, Dumlin A, Schürch C, Schmidt A, Skoda RC, Wymann MP, Hess C, Schöler HR, Zaehres H, Hurt E, Zavolan M, Lengerke C. Nuclear and cytosolic fractions of SOX2 synergize as transcriptional and translational co-regulators of cell fate. Cell Rep 2024; 43:114807. [PMID: 39368083 DOI: 10.1016/j.celrep.2024.114807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 01/28/2024] [Accepted: 09/13/2024] [Indexed: 10/07/2024] Open
Abstract
Stemness and pluripotency are mediated by transcriptional master regulators that promote self-renewal and repress cell differentiation, among which is the high-mobility group (HMG) box transcription factor SOX2. Dysregulated SOX2 expression, by contrast, leads to transcriptional aberrations relevant to oncogenic transformation, cancer progression, metastasis, therapy resistance, and relapse. Here, we report a post-transcriptional mechanism by which the cytosolic pool of SOX2 contributes to these events in an unsuspected manner. Specifically, a low-complexity region within SOX2's C-terminal segment connects to the ribosome to modulate the expression of cognate downstream factors. Independent of nuclear structures or DNA, this C-terminal functionality alone changes metabolic properties and induces non-adhesive growth when expressed in the cytosol of SOX2 knockout cells. We thus propose a revised model of SOX2 action where nuclear and cytosolic fractions cooperate to impose cell fate decisions via both transcriptional and translational mechanisms.
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Affiliation(s)
- Thorsten Schaefer
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
| | | | - Hui Wang
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Meric Ataman
- Biozentrum, University of Basel, Basel, Switzerland
| | - Silvia Candido
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Jonas Lötscher
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Sergiy Velychko
- Max Planck Institute for Molecular Biomedicine, Münster, Germany; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Lionel Tintignac
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Thomas Bock
- Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland
| | - Anastasiya Börsch
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Jochen Baßler
- Biochemistry Center Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Tata Nageswara Rao
- Medical Research Center, Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland; Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Jakub Zmajkovic
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Research Institute of Molecular Pathology (IMP), Vienna, Austria
| | - Sarah Roffeis
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Jordan Löliger
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Francis Jacob
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Alain Dumlin
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Christoph Schürch
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Alexander Schmidt
- Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland
| | - Radek C Skoda
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Matthias P Wymann
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
| | - Christoph Hess
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; CITIID, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Hans R Schöler
- Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Holm Zaehres
- Max Planck Institute for Molecular Biomedicine, Münster, Germany; Institute of Anatomy, Ruhr University Bochum, Bochum, Germany
| | - Ed Hurt
- Biochemistry Center Heidelberg, Heidelberg University, Heidelberg, Germany
| | | | - Claudia Lengerke
- Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland; Internal Medicine II, University Hospital Tübingen, Tübingen, Germany
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13
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Gao Y, van Velthoven CTJ, Lee C, Thomas ED, Bertagnolli D, Carey D, Casper T, Chakka AB, Chakrabarty R, Clark M, Desierto MJ, Ferrer R, Gloe J, Goldy J, Guilford N, Guzman J, Halterman CR, Hirschstein D, Ho W, James K, McCue R, Meyerdierks E, Nguy B, Pena N, Pham T, Shapovalova NV, Sulc J, Torkelson A, Tran A, Tung H, Wang J, Ronellenfitch K, Levi B, Hawrylycz MJ, Pagan C, Dee N, Smith KA, Tasic B, Yao Z, Zeng H. Continuous cell type diversification throughout the embryonic and postnatal mouse visual cortex development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.02.616246. [PMID: 39829740 PMCID: PMC11741437 DOI: 10.1101/2024.10.02.616246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
The mammalian cortex is composed of a highly diverse set of cell types and develops through a series of temporally regulated events that build out the cell type and circuit foundation for cortical function. The mechanisms underlying the development of different cell types remain elusive. Single-cell transcriptomics provides the capacity to systematically study cell types across the entire temporal range of cortical development. Here, we present a comprehensive and high-resolution transcriptomic and epigenomic cell type atlas of the developing mouse visual cortex. The atlas was built from a single-cell RNA-sequencing dataset of 568,674 high-quality single-cell transcriptomes and a single-nucleus Multiome dataset of 194,545 high-quality nuclei providing both transcriptomic and chromatin accessibility profiles, densely sampled throughout the embryonic and postnatal developmental stages from E11.5 to P56. We computationally reconstructed a transcriptomic developmental trajectory map of all excitatory, inhibitory, and non-neuronal cell types in the visual cortex, identifying branching points marking the emergence of new cell types at specific developmental ages and defining molecular signatures of cellular diversification. In addition to neurogenesis, gliogenesis and early postmitotic maturation in the embryonic stage which gives rise to all the cell classes and nearly all subclasses, we find that increasingly refined cell types emerge throughout the postnatal differentiation process, including the late emergence of many cell types during the eye-opening stage (P11-P14) and the onset of critical period (P21), suggesting continuous cell type diversification at different stages of cortical development. Throughout development, we find cooperative dynamic changes in gene expression and chromatin accessibility in specific cell types, identifying both chromatin peaks potentially regulating the expression of specific genes and transcription factors potentially regulating specific peaks. Furthermore, a single gene can be regulated by multiple peaks associated with different cell types and/or different developmental stages. Collectively, our study provides the most detailed dynamic molecular map directly associated with individual cell types and specific developmental events that reveals the molecular logic underlying the continuous refinement of cell type identities in the developing visual cortex.
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Affiliation(s)
- Yuan Gao
- Allen Institute for Brain Science, Seattle, WA, USA
| | | | - Changkyu Lee
- Allen Institute for Brain Science, Seattle, WA, USA
| | | | | | - Daniel Carey
- Allen Institute for Brain Science, Seattle, WA, USA
| | | | | | | | | | | | | | - Jessica Gloe
- Allen Institute for Brain Science, Seattle, WA, USA
| | - Jeff Goldy
- Allen Institute for Brain Science, Seattle, WA, USA
| | | | | | | | | | - Windy Ho
- Allen Institute for Brain Science, Seattle, WA, USA
| | | | - Rachel McCue
- Allen Institute for Brain Science, Seattle, WA, USA
| | | | - Beagan Nguy
- Allen Institute for Brain Science, Seattle, WA, USA
| | - Nick Pena
- Allen Institute for Brain Science, Seattle, WA, USA
| | | | | | - Josef Sulc
- Allen Institute for Brain Science, Seattle, WA, USA
| | | | - Alex Tran
- Allen Institute for Brain Science, Seattle, WA, USA
| | - Herman Tung
- Allen Institute for Brain Science, Seattle, WA, USA
| | - Justin Wang
- Allen Institute for Brain Science, Seattle, WA, USA
| | | | - Boaz Levi
- Allen Institute for Brain Science, Seattle, WA, USA
| | | | | | - Nick Dee
- Allen Institute for Brain Science, Seattle, WA, USA
| | | | | | - Zizhen Yao
- Allen Institute for Brain Science, Seattle, WA, USA
| | - Hongkui Zeng
- Allen Institute for Brain Science, Seattle, WA, USA
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14
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Baradaran-Bagherian S, Mehrab Mohseni M, Sharifi R, Amirinejad R, Shirvani-Farsani Z. The oxidative stress-associated long non-coding RNAs in pancreatic cancer. Adv Med Sci 2024; 69:231-237. [PMID: 38670228 DOI: 10.1016/j.advms.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 12/18/2023] [Accepted: 04/23/2024] [Indexed: 04/28/2024]
Abstract
PURPOSE A lot of people are dying from pancreatic cancer (PC) annually. The early detection of this cancer is particularly challenging due to the fact that symptoms tend to appear in advanced stages. It has been suggested that oxidative stress may play a role in the development of PC. Several genes regulate this process, including long noncoding RNAs (lncRNAs). There is no comprehensive study on the expression pattern of lncRNAs related to oxidative stress in PC patients. In the present case-control study, we quantified levels of oxidative stress-associated lncRNAs in PC patients versus healthy controls. PATIENTS AND METHODS In the present study, we investigated the expression levels of lincRNA-p21, LUCAT, RMST, FOXD3-AS1, and MT1DP lncRNAs in the peripheral blood mononuclear cells (PBMCs) of 53 PC patients and 50 healthy controls. The association between lncRNA expression and clinical and pathological characteristics was also evaluated. RESULTS The expression of lincRNA-P21 and rhabdomyosarcoma 2-associated transcript (RMST) lncRNAs in PC patients has significantly decreased. Expression of lncRNA RMST was significantly higher in TNM stage III-IV patients in comparison to TNM stage I-II patients. In addition, a significant positive association was recognized between candidate lncRNA expression, and finally, the AUC values of the expression levels of lincRNA-p21 and RMST were 0.60 and 0.61, respectively. CONCLUSIONS Altogether, our study suggests a possible role of lincRNA-p21 and RMST lncRNAs in the etiology of PC pathobiology, and their biomarker role may be understood in future studies.
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Affiliation(s)
- Setayesh Baradaran-Bagherian
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Mahdieh Mehrab Mohseni
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Roya Sharifi
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Roya Amirinejad
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zeinab Shirvani-Farsani
- Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.
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15
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Huang Y, Liu Y, Pu M, Zhang Y, Cao Q, Li S, Wei Y, Hou L. SOX2 interacts with hnRNPK to modulate alternative splicing in mouse embryonic stem cells. Cell Biosci 2024; 14:102. [PMID: 39160617 PMCID: PMC11331657 DOI: 10.1186/s13578-024-01284-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 08/07/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND SOX2 is a determinant transcription factor that governs the balance between stemness and differentiation by influencing transcription and splicing programs. The role of SOX2 is intricately shaped by its interactions with specific partners. In the interactome of SOX2 in mouse embryonic stem cells (mESCs), there is a cohort of heterogeneous nuclear ribonucleoproteins (hnRNPs) that contributes to multiple facets of gene expression regulation. However, the cross-talk between hnRNPs and SOX2 in gene expression regulation remains unclear. RESULTS Here we demonstrate the indispensable role of the co-existence of SOX2 and heterogeneous nuclear ribonucleoprotein K (hnRNPK) in the maintenance of pluripotency in mESCs. While hnRNPK directly interacts with the SOX2-HMG DNA-binding domain and induces the collapse of the transcriptional repressor 7SK small nuclear ribonucleoprotein (7SK snRNP), hnRNPK does not influence SOX2-mediated transcription, either by modulating the interaction between SOX2 and its target cis-regulatory elements or by facilitating transcription elongation as indicated by the RNA-seq analysis. Notably, hnRNPK enhances the interaction of SOX2 with target pre-mRNAs and collaborates with SOX2 in regulating the alternative splicing of a subset of pluripotency genes. CONCLUSIONS These data reveal that SOX2 and hnRNPK have a direct protein-protein interaction, and shed light on the molecular mechanisms by which hnRNPK collaborates with SOX2 in alternative splicing in mESCs.
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Affiliation(s)
- Yanlan Huang
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China
| | - Yuxuan Liu
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China
| | - Mingyi Pu
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China
| | - Yuli Zhang
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China
| | - Qiang Cao
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China
| | - Senru Li
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China
| | - Yuanjie Wei
- Helmholtz Centre for Infection Research (HZI), Helmholtz Institute for RNA-Based Infection Research (HIRI), Würzburg, Germany.
| | - Linlin Hou
- School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, People's Republic of China.
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16
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Yokoyama S, Muto H, Honda T, Kurokawa Y, Ogawa H, Nakajima R, Kawashima H, Tani H. Identification of Two Long Noncoding RNAs, Kcnq1ot1 and Rmst, as Biomarkers in Chronic Liver Diseases in Mice. Int J Mol Sci 2024; 25:8927. [PMID: 39201613 PMCID: PMC11354866 DOI: 10.3390/ijms25168927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 08/12/2024] [Accepted: 08/14/2024] [Indexed: 09/02/2024] Open
Abstract
This study investigates novel short-lived long noncoding RNAs (lncRNAs) in mice with altered expression in metabolic dysfunction-associated steatotic liver (MASH) and liver fibrosis. LncRNAs share similarities with mRNAs in their transcription by RNA polymerase II, possession of a 5' cap structure, and presence of a polyA tail. We identified two lncRNAs, Kcnq1ot1 and Rmst, significantly decreased in both conditions. These lncRNAs showed dramatic expression changes in MASH livers induced by Western diets and CCl4, and in fibrotic livers induced by CCl4 alone. The decrease was more pronounced in liver fibrosis, suggesting their potential as biomarkers for disease progression. Our findings are consistent across different fibrosis models, indicating a crucial role for these lncRNAs in MASH and liver fibrosis in mice. With MASH becoming a global health issue and its progression to fibrosis associated with hepatocarcinogenesis and poor prognosis, understanding the underlying mechanisms is critical. This research contributes to elucidating lncRNA functions in murine liver diseases and provides a foundation for developing novel therapeutic strategies targeting lncRNAs in MASH and liver fibrosis, offering new avenues for potential therapeutic interventions.
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Affiliation(s)
- Shinya Yokoyama
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan; (S.Y.); (H.M.); (T.H.); (H.K.)
| | - Hisanori Muto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan; (S.Y.); (H.M.); (T.H.); (H.K.)
- Department of Gastroenterology and Hepatology, Fujita Health University Bantane Hospital, 3-6-10, Otoubashi, Nakagawa-ku, Nagoya 454-8509, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan; (S.Y.); (H.M.); (T.H.); (H.K.)
| | - Yoichi Kurokawa
- Department of Bioscience and Biotechnology, Fukui Prefectural University, Eiheiji-cho, Fukui 910-1195, Japan;
| | - Hirotaka Ogawa
- Nagoya Industrial Science Research Institute, Nagoya 460-0008, Japan;
| | - Riku Nakajima
- Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano, Totsuka, Yokohama 245-0066, Japan;
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8560, Japan; (S.Y.); (H.M.); (T.H.); (H.K.)
| | - Hidenori Tani
- Department of Health Pharmacy, Yokohama University of Pharmacy, 601 Matano, Totsuka, Yokohama 245-0066, Japan;
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17
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Ali G, Shin KC, Ahmed N, Habbab W, Alkhadairi G, Razzaq A, Bejaoui Y, El Hajj N, Mifsud B, Park Y, Stanton LW. Deletion in RMST lncRNA impairs hypothalamic neuronal development in a human stem cell-based model of Kallmann Syndrome. Cell Death Discov 2024; 10:330. [PMID: 39030180 PMCID: PMC11271498 DOI: 10.1038/s41420-024-02074-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 06/12/2024] [Accepted: 06/18/2024] [Indexed: 07/21/2024] Open
Abstract
Rhabdomyosarcoma 2-associated transcript (RMST) long non-coding RNA has previously been shown to cause Kallmann syndrome (KS), a rare genetic disorder characterized by congenital hypogonadotropic hypogonadism (CHH) and olfactory dysfunction. In the present study, we generated large deletions of approximately 41.55 kb in the RMST gene in human pluripotent stem cells using CRISPR/Cas9 gene editing. To evaluate the impact of RMST deletion, these cells were differentiated into hypothalamic neurons that include 10-15% neurons that express gonadotrophin-releasing hormone (GnRH). We found that deletion in RMST did not impair the neurogenesis of GnRH neurons, however, the hypothalamic neurons were electro-physiologically hyperactive and had increased calcium influx activity compared to control. Transcriptomic and epigenetic analyses showed that RMST deletion caused altered expression of key genes involved in neuronal development, ion channels, synaptic signaling and cell adhesion. The in vitro generation of these RMST-deleted GnRH neurons provides an excellent cell-based model to dissect the molecular mechanism of RMST function in Kallmann syndrome and its role in hypothalamic neuronal development.
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Affiliation(s)
- Gowher Ali
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad, Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Kyung Chul Shin
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad, Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Nisar Ahmed
- College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Wesal Habbab
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad, Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Ghaneya Alkhadairi
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad, Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Aleem Razzaq
- College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Yosra Bejaoui
- College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Nady El Hajj
- College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
- College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Borbala Mifsud
- College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
- William Harvey Research Institute, Queen Mary University London, London, UK
| | - Yongsoo Park
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad, Bin Khalifa University, Qatar Foundation, Doha, Qatar
- College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
| | - Lawrence W Stanton
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad, Bin Khalifa University, Qatar Foundation, Doha, Qatar.
- College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.
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18
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Ghafoori SM, Sethi A, Petersen GF, Tanipour MH, Gooley PR, Forwood JK. RNA Binding Properties of SOX Family Members. Cells 2024; 13:1202. [PMID: 39056784 PMCID: PMC11274882 DOI: 10.3390/cells13141202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 07/09/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
SOX proteins are a family of transcription factors (TFs) that play critical functions in sex determination, neurogenesis, and chondrocyte differentiation, as well as cardiac, vascular, and lymphatic development. There are 20 SOX family members in humans, each sharing a 79-residue L-shaped high mobility group (HMG)-box domain that is responsible for DNA binding. SOX2 was recently shown to interact with long non-coding RNA and large-intergenic non-coding RNA to regulate embryonic stem cell and neuronal differentiation. The RNA binding region was shown to reside within the HMG-box domain; however, the structural details of this binding remain unclear. Here, we show that all SOX family members, except group H, interact with RNA. Our mutational experiments demonstrate that the disordered C-terminal region of the HMG-box domain plays an important role in RNA binding. Further, by determining a high-resolution structure of the HMG-box domain of the group H family member SOX30, we show that despite differences in RNA binding ability, SOX30 shares a very similar secondary structure with other SOX protein HMG-box domains. Together, our study provides insight into the interaction of SOX TFs with RNA.
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Affiliation(s)
- Seyed Mohammad Ghafoori
- School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia;
| | - Ashish Sethi
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia; (A.S.); (M.H.T.); (P.R.G.)
- Australian Nuclear Science Technology Organisation, The Australian Synchrotron, 800 Blackburn Rd., Clayton, VIC 3168, Australia
| | - Gayle F. Petersen
- Gulbali Institute, Charles Sturt University, Wagga Wagga, NSW 2678, Australia;
| | - Mohammad Hossein Tanipour
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia; (A.S.); (M.H.T.); (P.R.G.)
| | - Paul R. Gooley
- Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC 3010, Australia; (A.S.); (M.H.T.); (P.R.G.)
| | - Jade K. Forwood
- School of Dentistry and Medical Sciences, Charles Sturt University, Wagga Wagga, NSW 2678, Australia;
- Gulbali Institute, Charles Sturt University, Wagga Wagga, NSW 2678, Australia;
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19
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Alammari F, Al-Hujaily EM, Alshareeda A, Albarakati N, Al-Sowayan BS. Hidden regulators: the emerging roles of lncRNAs in brain development and disease. Front Neurosci 2024; 18:1392688. [PMID: 38841098 PMCID: PMC11150811 DOI: 10.3389/fnins.2024.1392688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 04/22/2024] [Indexed: 06/07/2024] Open
Abstract
Long non-coding RNAs (lncRNAs) have emerged as critical players in brain development and disease. These non-coding transcripts, which once considered as "transcriptional junk," are now known for their regulatory roles in gene expression. In brain development, lncRNAs participate in many processes, including neurogenesis, neuronal differentiation, and synaptogenesis. They employ their effect through a wide variety of transcriptional and post-transcriptional regulatory mechanisms through interactions with chromatin modifiers, transcription factors, and other regulatory molecules. Dysregulation of lncRNAs has been associated with certain brain diseases, including Alzheimer's disease, Parkinson's disease, cancer, and neurodevelopmental disorders. Altered expression and function of specific lncRNAs have been implicated with disrupted neuronal connectivity, impaired synaptic plasticity, and aberrant gene expression pattern, highlighting the functional importance of this subclass of brain-enriched RNAs. Moreover, lncRNAs have been identified as potential biomarkers and therapeutic targets for neurological diseases. Here, we give a comprehensive review of the existing knowledge of lncRNAs. Our aim is to provide a better understanding of the diversity of lncRNA structure and functions in brain development and disease. This holds promise for unravelling the complexity of neurodevelopmental and neurodegenerative disorders, paving the way for the development of novel biomarkers and therapeutic targets for improved diagnosis and treatment.
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Affiliation(s)
- Farah Alammari
- Department of Blood and Cancer Research, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Ensaf M. Al-Hujaily
- Department of Blood and Cancer Research, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Alaa Alshareeda
- Department of Blood and Cancer Research, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- Saudi Biobank Department, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Nada Albarakati
- Department of Blood and Cancer Research, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Ministry of the National Guard-Health Affairs, Jeddah, Saudi Arabia
| | - Batla S. Al-Sowayan
- Department of Blood and Cancer Research, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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20
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Espadas I, Wingfield JL, Nakahata Y, Chanda K, Grinman E, Ghosh I, Bauer KE, Raveendra B, Kiebler MA, Yasuda R, Rangaraju V, Puthanveettil S. Synaptically-targeted long non-coding RNA SLAMR promotes structural plasticity by increasing translation and CaMKII activity. Nat Commun 2024; 15:2694. [PMID: 38538603 PMCID: PMC10973417 DOI: 10.1038/s41467-024-46972-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 03/15/2024] [Indexed: 04/04/2024] Open
Abstract
Long noncoding RNAs (lncRNAs) play crucial roles in maintaining cell homeostasis and function. However, it remains largely unknown whether and how neuronal activity impacts the transcriptional regulation of lncRNAs, or if this leads to synapse-related changes and contributes to the formation of long-term memories. Here, we report the identification of a lncRNA, SLAMR, which becomes enriched in CA1-hippocampal neurons upon contextual fear conditioning but not in CA3 neurons. SLAMR is transported along dendrites via the molecular motor KIF5C and is recruited to the synapse upon stimulation. Loss of function of SLAMR reduces dendritic complexity and impairs activity-dependent changes in spine structural plasticity and translation. Gain of function of SLAMR, in contrast, enhances dendritic complexity, spine density, and translation. Analyses of the SLAMR interactome reveal its association with CaMKIIα protein through a 220-nucleotide element also involved in SLAMR transport. A CaMKII reporter reveals a basal reduction in CaMKII activity with SLAMR loss-of-function. Furthermore, the selective loss of SLAMR function in CA1 disrupts the consolidation of fear memory in male mice, without affecting their acquisition, recall, or extinction, or spatial memory. Together, these results provide new molecular and functional insight into activity-dependent changes at the synapse and consolidation of contextual fear.
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Affiliation(s)
- Isabel Espadas
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Jenna L Wingfield
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | | | - Kaushik Chanda
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Eddie Grinman
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Ilika Ghosh
- Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA
| | - Karl E Bauer
- Biomedical Center, Department for Cell Biology, Ludwig-Maximilians-University of Munich, Medical Faculty, 82152, Planegg-Martinsried, Germany
| | - Bindu Raveendra
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Michael A Kiebler
- Biomedical Center, Department for Cell Biology, Ludwig-Maximilians-University of Munich, Medical Faculty, 82152, Planegg-Martinsried, Germany
| | - Ryohei Yasuda
- Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA
| | | | - Sathyanarayanan Puthanveettil
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA.
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21
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Sato J, Satoh Y, Yamamoto T, Watanabe T, Matsubara S, Satake H, Kimura AP. PTBP2 binds to a testis-specific long noncoding RNA, Tesra, and activates transcription of the Prss42/Tessp-2 gene. Gene 2024; 893:147907. [PMID: 37858745 DOI: 10.1016/j.gene.2023.147907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/22/2023] [Accepted: 10/16/2023] [Indexed: 10/21/2023]
Abstract
Long noncoding RNAs (lncRNAs) have recently been proved to be functional in the testis. Tesra, a testis-specific lncRNA, was suggested to activate the transcription of Prss42/Tessp-2, a gene that is involved in meiotic progression, in mouse spermatocytes. To reveal the molecular mechanism underlying the activation, we searched for Tesra-binding proteins by a Ribotrap assay followed by LC-MS/MS analysis and identified polypyrimidine tract binding protein 2 (PTBP2) as a candidate. Analysis of public RNA-seq data and our qRT-PCR results indicated that Ptbp2 mRNA showed an expression pattern similar to the expression patterns of Tesra and Prss42/Tessp-2 during testis development. Moreover, PTBP2 was found to be associated with Tesra in testicular germ cells by RNA immunoprecipitation. To evaluate the effect of PTBP2 on the Prss42/Tessp-2 promoter, we established an in vitro reporter gene assay system in which Tesra expression could be induced by the Tet-on system and thereby Prss42/Tessp-2 promoter activity could be increased. In this system, the Prss42/Tessp-2 promoter activity was significantly decreased by the knockdown of PTBP2. These results suggest that PTBP2 contributes to Prss42/Tessp-2 transcriptional activation by Tesra in spermatocytes. The finding provides a precious example of a molecular mechanism of testis lncRNA functioning in spermatogenesis.
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Affiliation(s)
- Josei Sato
- Graduate School of Life Science, Hokkaido University, Sapporo, Japan
| | - Yui Satoh
- Graduate School of Life Science, Hokkaido University, Sapporo, Japan
| | - Takehiro Yamamoto
- Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan
| | - Takehiro Watanabe
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Shin Matsubara
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Honoo Satake
- Bioorganic Research Institute, Suntory Foundation for Life Sciences, Kyoto, Japan
| | - Atsushi P Kimura
- Graduate School of Life Science, Hokkaido University, Sapporo, Japan; Department of Biological Sciences, Faculty of Science, Hokkaido University, Sapporo, Japan.
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22
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Shah M, Sarkar D. HCC-Related lncRNAs: Roles and Mechanisms. Int J Mol Sci 2024; 25:597. [PMID: 38203767 PMCID: PMC10779127 DOI: 10.3390/ijms25010597] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Hepatocellular carcinoma (HCC) presents a significant global health threat, particularly in regions endemic to hepatitis B and C viruses, and because of the ongoing pandemic of obesity causing metabolic-dysfunction-related fatty liver disease (MAFLD), a precursor to HCC. The molecular intricacies of HCC, genetic and epigenetic alterations, and dysregulated signaling pathways facilitate personalized treatment strategies based on molecular profiling. Epigenetic regulation, encompassing DNA methyltion, histone modifications, and noncoding RNAs, functions as a critical layer influencing HCC development. Long noncoding RNAs (lncRNAs) are spotlighted for their diverse roles in gene regulation and their potential as diagnostic and therapeutic tools in cancer. In this review, we explore the pivotal role of lncRNAs in HCC, including MAFLD and viral hepatitis, the most prevalent risk factors for hepatocarcinogenesis. The dysregulation of lncRNAs is implicated in HCC progression by modulating chromatin regulation and transcription, sponging miRNAs, and influencing structural functions. The ongoing studies on lncRNAs contribute to a deeper comprehension of HCC pathogenesis and offer promising routes for precision medicine, highlighting the utility of lncRNAs as early biomarkers, prognostic indicators, and therapeutic targets.
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Affiliation(s)
- Mimansha Shah
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, USA;
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Massey Comprehensive Cancer Center, and VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, VA 23298, USA
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23
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Jiang M, Wang Z, Lu T, Li X, Yang K, Zhao L, Zhang D, Li J, Wang L. Integrative analysis of long noncoding RNAs dysregulation and synapse-associated ceRNA regulatory axes in autism. Transl Psychiatry 2023; 13:375. [PMID: 38057311 DOI: 10.1038/s41398-023-02662-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 10/30/2023] [Accepted: 11/09/2023] [Indexed: 12/08/2023] Open
Abstract
Autism spectrum disorder (ASD) is a complex disorder of neurodevelopment, the function of long noncoding RNA (lncRNA) in ASD remains essentially unknown. In the present study, gene networks were used to explore the ASD disease mechanisms integrating multiple data types (for example, RNA expression, whole-exome sequencing signals, weighted gene co-expression network analysis, and protein-protein interaction) and datasets (five human postmortem datasets). A total of 388 lncRNAs and five co-expression modules were found to be altered in ASD. The downregulated co-expression M4 module was significantly correlated with ASD, enriched with autism susceptibility genes and synaptic signaling. Integrating lncRNAs from the M4 module and microRNA (miRNA) dysregulation data from the literature identified competing endogenous RNA (ceRNA) network. We identified the downregulated mRNAs that interact with miRNAs by the miRTarBase, miRDB, and TargetScan databases. Our analysis reveals that MIR600HG was downregulated in multiple brain tissue datasets and was closely associated with 9 autism-susceptible miRNAs in the ceRNA network. MIR600HG and target mRNAs (EPHA4, MOAP1, MAP3K9, STXBP1, PRKCE, and SCAMP5) were downregulated in the peripheral blood by quantitative reverse transcription polymerase chain reaction analysis (false discovery rate <0.05). Subsequently, we assessed the role of lncRNA dysregulation in altered mRNA levels. Experimental verification showed that some synapse-associated mRNAs were downregulated after the MIR600HG knockdown. BrainSpan project showed that the expression patterns of MIR600HG (primate-specific lncRNA) and synapse-associated mRNA were similar in different human brain regions and at different stages of development. A combination of support vector machine and random forest machine learning algorithms retrieved the marker gene for ASD in the ceRNA network, and the area under the curve of the diagnostic nomogram was 0.851. In conclusion, dysregulation of MIR600HG, a novel specific lncRNA associated with ASD, is responsible for the ASD-associated miRNA-mRNA axes, thereby potentially regulating synaptogenesis.
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Affiliation(s)
- Miaomiao Jiang
- National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China
| | - Ziqi Wang
- Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
| | - Tianlan Lu
- National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China
| | - Xianjing Li
- National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China
| | - Kang Yang
- National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China
| | - Liyang Zhao
- National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China
| | - Dai Zhang
- National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China
- Guangdong Key Laboratory of Mental Health and Cognitive Science, Institute for Brain Research and Rehabilitation (IBRR), South China Normal University, Guangzhou, China
| | - Jun Li
- National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China.
| | - Lifang Wang
- National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), NHC Key Laboratory of Mental Health (Peking University), Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, China.
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24
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Mukhopadhyay A, Deshpande SN, Bhatia T, Thelma BK. Significance of an altered lncRNA landscape in schizophrenia and cognition: clues from a case-control association study. Eur Arch Psychiatry Clin Neurosci 2023; 273:1677-1691. [PMID: 37009928 DOI: 10.1007/s00406-023-01596-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 03/20/2023] [Indexed: 04/04/2023]
Abstract
Genetic etiology of schizophrenia is poorly understood despite large genome-wide association data. Long non-coding RNAs (lncRNAs) with a probable regulatory role are emerging as important players in neuro-psychiatric disorders including schizophrenia. Prioritising important lncRNAs and analyses of their holistic interaction with their target genes may provide insights into disease biology/etiology. Of the 3843 lncRNA SNPs reported in schizophrenia GWASs extracted using lincSNP 2.0, we prioritised n = 247 based on association strength, minor allele frequency and regulatory potential and mapped them to lncRNAs. lncRNAs were then prioritised based on their expression in brain using lncRBase, epigenetic role using 3D SNP and functional relevance to schizophrenia etiology. 18 SNPs were finally tested for association with schizophrenia (n = 930) and its endophenotypes-tardive dyskinesia (n = 176) and cognition (n = 565) using a case-control approach. Associated SNPs were characterised by ChIP seq, eQTL, and transcription factor binding site (TFBS) data using FeatSNP. Of the eight SNPs significantly associated, rs2072806 in lncRNA hsaLB_IO39983 with regulatory effect on BTN3A2 was associated with schizophrenia (p = 0.006); rs2710323 in hsaLB_IO_2331 with role in dysregulation of ITIH1 with tardive dyskinesia (p < 0.05); and four SNPs with significant cognition score reduction (p < 0.05) in cases. Two of these with two additional variants in eQTL were observed among controls (p < 0.05), acting likely as enhancer SNPs and/or altering TFBS of eQTL mapped downstream genes. This study highlights important lncRNAs in schizophrenia and provides a proof of concept of novel interactions of lncRNAs with protein-coding genes to elicit alterations in immune/inflammatory pathways of schizophrenia.
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Affiliation(s)
- Anirban Mukhopadhyay
- Department of Genetics, University of Delhi South Campus, Benito Juarez Marg, New Delhi, 110021, India
| | - Smita N Deshpande
- Department of Psychiatry, Postgraduate Institute of Medical Education and Research-Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - Triptish Bhatia
- Department of Psychiatry, Postgraduate Institute of Medical Education and Research-Dr. Ram Manohar Lohia Hospital, New Delhi, India
| | - B K Thelma
- Department of Genetics, University of Delhi South Campus, Benito Juarez Marg, New Delhi, 110021, India.
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25
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Pandini C, Rey F, Cereda C, Carelli S, Gandellini P. Study of lncRNAs in Pediatric Neurological Diseases: Methods, Analysis of the State-of-Art and Possible Therapeutic Implications. Pharmaceuticals (Basel) 2023; 16:1616. [PMID: 38004481 PMCID: PMC10675345 DOI: 10.3390/ph16111616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/06/2023] [Accepted: 11/13/2023] [Indexed: 11/26/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in various cellular processes, and their roles in pediatric neurological diseases are increasingly being explored. This review provides an overview of lncRNA implications in the central nervous system, both in its physiological state and when a pathological condition is present. We describe the role of lncRNAs in neural development, highlighting their significance in processes such as neural stem cell proliferation, differentiation, and synaptogenesis. Dysregulation of specific lncRNAs is associated with multiple pediatric neurological diseases, such as neurodevelopmental or neurodegenerative disorders and brain tumors. The collected evidence indicates that there is a need for further research to uncover the full spectrum of lncRNA involvement in pediatric neurological diseases and brain tumors. While challenges exist, ongoing advancements in technology and our understanding of lncRNA biology offer hope for future breakthroughs in the field of pediatric neurology, leveraging lncRNAs as potential therapeutic targets and biomarkers.
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Affiliation(s)
- Cecilia Pandini
- Department of Biosciences, University of Milan, 20133 Milan, Italy;
| | - Federica Rey
- Pediatric Clinical Research Center “Fondazione Romeo ed Enrica Invernizzi”, Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy; (F.R.); (S.C.)
- Center of Functional Genomics and Rare Diseases, Department of Pediatrics, Buzzi Children’s Hospital, 20157 Milan, Italy;
| | - Cristina Cereda
- Center of Functional Genomics and Rare Diseases, Department of Pediatrics, Buzzi Children’s Hospital, 20157 Milan, Italy;
| | - Stephana Carelli
- Pediatric Clinical Research Center “Fondazione Romeo ed Enrica Invernizzi”, Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy; (F.R.); (S.C.)
- Center of Functional Genomics and Rare Diseases, Department of Pediatrics, Buzzi Children’s Hospital, 20157 Milan, Italy;
| | - Paolo Gandellini
- Department of Biosciences, University of Milan, 20133 Milan, Italy;
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26
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Modi A, Lopez G, Conkrite KL, Su C, Leung TC, Ramanan S, Manduchi E, Johnson ME, Cheung D, Gadd S, Zhang J, Smith MA, Guidry Auvil JM, Meshinchi S, Perlman EJ, Hunger SP, Maris JM, Wells AD, Grant SF, Diskin SJ. Integrative Genomic Analyses Identify LncRNA Regulatory Networks across Pediatric Leukemias and Solid Tumors. Cancer Res 2023; 83:3462-3477. [PMID: 37584517 PMCID: PMC10787516 DOI: 10.1158/0008-5472.can-22-3186] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 03/07/2023] [Accepted: 08/09/2023] [Indexed: 08/17/2023]
Abstract
Long noncoding RNAs (lncRNA) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the lncRNA landscape across pediatric cancers remains largely uncharted. Here, we curated RNA sequencing data for 1,044 pediatric leukemia and extracranial solid tumors and integrated paired tumor whole genome sequencing and epigenetic data in relevant cell line models to explore lncRNA expression, regulation, and association with cancer. A total of 2,657 lncRNAs were robustly expressed across six pediatric cancers, including 1,142 exhibiting histotype-elevated expression. DNA copy number alterations contributed to lncRNA dysregulation at a proportion comparable to protein coding genes. Application of a multidimensional framework to identify and prioritize lncRNAs impacting gene networks revealed that lncRNAs dysregulated in pediatric cancer are associated with proliferation, metabolism, and DNA damage hallmarks. Analysis of upstream regulation via cell type-specific transcription factors further implicated distinct histotype-elevated and developmental lncRNAs. Integration of these analyses prioritized lncRNAs for experimental validation, and silencing of TBX2-AS1, the top-prioritized neuroblastoma-specific lncRNA, resulted in significant growth inhibition of neuroblastoma cells, confirming the computational predictions. Taken together, these data provide a comprehensive characterization of lncRNA regulation and function in pediatric cancers and pave the way for future mechanistic studies. SIGNIFICANCE Comprehensive characterization of lncRNAs in pediatric cancer leads to the identification of highly expressed lncRNAs across childhood cancers, annotation of lncRNAs showing histotype-specific elevated expression, and prediction of lncRNA gene regulatory networks.
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Affiliation(s)
- Apexa Modi
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
- Genomics and Computational Biology Graduate Group, Biomedical Graduate Studies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Gonzalo Lopez
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
| | - Karina L. Conkrite
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
| | - Chun Su
- Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Tsz Ching Leung
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
| | - Sathvik Ramanan
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
| | - Elisabetta Manduchi
- Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Matthew E. Johnson
- Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Daphne Cheung
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
| | - Samantha Gadd
- Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois 60208, USA
| | - Jinghui Zhang
- Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA
| | - Malcolm A. Smith
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland 20892, USA
| | | | - Soheil Meshinchi
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
| | - Elizabeth J. Perlman
- Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois 60208, USA
| | - Stephen P. Hunger
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - John M. Maris
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Andrew D Wells
- Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Struan F.A. Grant
- Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Divisions of Human Genetics and Endocrinology & Diabetes, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA
| | - Sharon J. Diskin
- Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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Wang C, Zhao F, He Y, E Y, Li S. Long non-coding RNA RMST serves as a diagnostic biomarker in patients with carotid artery stenosis and predicts the occurrence of cerebral ischemic event: A retrospective study. Vascular 2023; 31:908-913. [PMID: 35531613 DOI: 10.1177/17085381221100095] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVES The purpose of this retrospective study is to explore the diagnostic and prognostic roles of serum RMST in carotid artery stenosis (CAS). METHODS Serum levels of RMST were detected in CAS patients, and the relationship between degree of carotid stenosis and RMST levels was analyzed. The ROC curve was drawn to evaluate RMST value in predicting the risk of CAS. Then, all CAS patients received a 5-year follow-up. K-M curve was used to analyze the significance of RMST on prognosis of CAS patients. Multi-factor cox logistic regression analysis was conducted to evaluate independent factors for outcome of CAS patients. RESULTS An increased RMST expression was certified in CAS patients when compared with healthy controls. The increase of serum RMST expression was related to high degree of carotid stenosis. In addition, serum RMST was a possible diagnosis and an independent influencing factor of prognosis in patients with CAS. CONCLUSIONS Raised serum RMST level was found in patients with CAS. Detecting RMST expression levels was of high value for predicting the occurrence and outcomes in CAS.
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Affiliation(s)
- Cui Wang
- Pre-hospital Emergency Center, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Feng Zhao
- Department of Interventional Vascular Surgery, Affiliated Hospital of Hebei University, Baoding, China
| | - Yunliang He
- Department of Interventional Vascular Surgery, Affiliated Hospital of Hebei University, Baoding, China
| | - Yajun E
- Department of Interventional Vascular Surgery, Affiliated Hospital of Hebei University, Baoding, China
| | - Shanfeng Li
- Department of Interventional Vascular Surgery, Affiliated Hospital of Hebei University, Baoding, China
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Limouse C, Smith OK, Jukam D, Fryer KA, Greenleaf WJ, Straight AF. Global mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions. Nat Commun 2023; 14:6073. [PMID: 37770513 PMCID: PMC10539311 DOI: 10.1038/s41467-023-41848-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 09/19/2023] [Indexed: 09/30/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are transcribed throughout the genome and provide regulatory inputs to gene expression through their interaction with chromatin. Yet, the genomic targets and functions of most ncRNAs are unknown. Here we use chromatin-associated RNA sequencing (ChAR-seq) to map the global network of ncRNA interactions with chromatin in human embryonic stem cells and the dynamic changes in interactions during differentiation into definitive endoderm. We uncover general principles governing the organization of the RNA-chromatin interactome, demonstrating that nearly all ncRNAs exclusively interact with genes in close three-dimensional proximity to their locus and provide a model predicting the interactome. We uncover RNAs that interact with many loci across the genome and unveil thousands of unannotated RNAs that dynamically interact with chromatin. By relating the dynamics of the interactome to changes in gene expression, we demonstrate that activation or repression of individual genes is unlikely to be controlled by a single ncRNA.
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Affiliation(s)
- Charles Limouse
- Department of Biochemistry, Stanford University, Stanford, California, USA
| | - Owen K Smith
- Department of Chemical and Systems Biology, Stanford University, Stanford, California, USA
| | - David Jukam
- Department of Biochemistry, Stanford University, Stanford, California, USA
| | - Kelsey A Fryer
- Department of Biochemistry, Stanford University, Stanford, California, USA
- Department of Genetics, Stanford University, Stanford, California, USA
| | | | - Aaron F Straight
- Department of Biochemistry, Stanford University, Stanford, California, USA.
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29
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Hamilton DJ, Hein AE, Wuttke DS, Batey RT. The DNA binding high mobility group box protein family functionally binds RNA. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1778. [PMID: 36646476 PMCID: PMC10349909 DOI: 10.1002/wrna.1778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/22/2022] [Accepted: 12/27/2022] [Indexed: 01/18/2023]
Abstract
Nucleic acid binding proteins regulate transcription, splicing, RNA stability, RNA localization, and translation, together tailoring gene expression in response to stimuli. Upon discovery, these proteins are typically classified as either DNA or RNA binding as defined by their in vivo functions; however, recent evidence suggests dual DNA and RNA binding by many of these proteins. High mobility group box (HMGB) proteins have a DNA binding HMGB domain, act as transcription factors and chromatin remodeling proteins, and are increasingly understood to interact with RNA as means to regulate gene expression. Herein, multiple layers of evidence that the HMGB family are dual DNA and RNA binding proteins is comprehensively reviewed. For example, HMGB proteins directly interact with RNA in vitro and in vivo, are localized to RNP granules involved in RNA processing, and their protein interactors are enriched in RNA binding proteins involved in RNA metabolism. Importantly, in cell-based systems, HMGB-RNA interactions facilitate protein-protein interactions, impact splicing outcomes, and modify HMGB protein genomic or cellular localization. Misregulation of these HMGB-RNA interactions are also likely involved in human disease. This review brings to light that as a family, HMGB proteins are likely to bind RNA which is essential to HMGB protein biology. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
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30
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Batugedara G, Lu XM, Hristov B, Abel S, Chahine Z, Hollin T, Williams D, Wang T, Cort A, Lenz T, Thompson TA, Prudhomme J, Tripathi AK, Xu G, Cudini J, Dogga S, Lawniczak M, Noble WS, Sinnis P, Le Roch KG. Novel insights into the role of long non-coding RNA in the human malaria parasite, Plasmodium falciparum. Nat Commun 2023; 14:5086. [PMID: 37607941 PMCID: PMC10444892 DOI: 10.1038/s41467-023-40883-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 08/10/2023] [Indexed: 08/24/2023] Open
Abstract
The complex life cycle of Plasmodium falciparum requires coordinated gene expression regulation to allow host cell invasion, transmission, and immune evasion. Increasing evidence now suggests a major role for epigenetic mechanisms in gene expression in the parasite. In eukaryotes, many lncRNAs have been identified to be pivotal regulators of genome structure and gene expression. To investigate the regulatory roles of lncRNAs in P. falciparum we explore the intergenic lncRNA distribution in nuclear and cytoplasmic subcellular locations. Using nascent RNA expression profiles, we identify a total of 1768 lncRNAs, of which 718 (~41%) are novels in P. falciparum. The subcellular localization and stage-specific expression of several putative lncRNAs are validated using RNA-FISH. Additionally, the genome-wide occupancy of several candidate nuclear lncRNAs is explored using ChIRP. The results reveal that lncRNA occupancy sites are focal and sequence-specific with a particular enrichment for several parasite-specific gene families, including those involved in pathogenesis and sexual differentiation. Genomic and phenotypic analysis of one specific lncRNA demonstrate its importance in sexual differentiation and reproduction. Our findings bring a new level of insight into the role of lncRNAs in pathogenicity, gene regulation and sexual differentiation, opening new avenues for targeted therapeutic strategies against the deadly malaria parasite.
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Affiliation(s)
- Gayani Batugedara
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Xueqing M Lu
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Borislav Hristov
- Department of Genome Sciences, University of Washington, Seattle, WA, 98195-5065, USA
| | - Steven Abel
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Zeinab Chahine
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Thomas Hollin
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Desiree Williams
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Tina Wang
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Anthony Cort
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Todd Lenz
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Trevor A Thompson
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Jacques Prudhomme
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA
| | - Abhai K Tripathi
- Department of Molecular Microbiology and Immunology and the Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
| | - Guoyue Xu
- Department of Molecular Microbiology and Immunology and the Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
| | | | - Sunil Dogga
- Wellcome Sanger Institute, Hinxton, CB10 1SA, UK
| | | | | | - Photini Sinnis
- Department of Molecular Microbiology and Immunology and the Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA
| | - Karine G Le Roch
- Department of Molecular Cell and Systems Biology, University of California Riverside, Riverside, CA, 92521, USA.
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31
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Ben-Mahmoud A, Kishikawa S, Gupta V, Leach NT, Shen Y, Moldovan O, Goel H, Hopper B, Ranguin K, Gruchy N, Maas SM, Lacassie Y, Kim SH, Kim WY, Quade BJ, Morton CC, Kim CH, Layman LC, Kim HG. A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome. Sci Rep 2023; 13:12984. [PMID: 37563198 PMCID: PMC10415337 DOI: 10.1038/s41598-023-40037-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 08/03/2023] [Indexed: 08/12/2023] Open
Abstract
In a patient diagnosed with both Kallmann syndrome (KS) and intellectual disability (ID), who carried an apparently balanced translocation t(7;12)(q22;q24)dn, array comparative genomic hybridization (aCGH) disclosed a cryptic heterozygous 4.7 Mb deletion del(12)(p11.21p11.23), unrelated to the translocation breakpoint. This novel discovery prompted us to consider the possibility that the combination of KS and neurological disorder in this patient could be attributed to gene(s) within this specific deletion at 12p11.21-12p11.23, rather than disrupted or dysregulated genes at the translocation breakpoints. To further support this hypothesis, we expanded our study by screening five candidate genes at both breakpoints of the chromosomal translocation in a cohort of 48 KS patients. However, no mutations were found, thus reinforcing our supposition. In order to delve deeper into the characterization of the 12p11.21-12p11.23 region, we enlisted six additional patients with small copy number variations (CNVs) and analyzed eight individuals carrying small CNVs in this region from the DECIPHER database. Our investigation utilized a combination of complementary approaches. Firstly, we conducted a comprehensive phenotypic-genotypic comparison of reported CNV cases. Additionally, we reviewed knockout animal models that exhibit phenotypic similarities to human conditions. Moreover, we analyzed reported variants in candidate genes and explored their association with corresponding phenotypes. Lastly, we examined the interacting genes associated with these phenotypes to gain further insights. As a result, we identified a dozen candidate genes: TSPAN11 as a potential KS candidate gene, TM7SF3, STK38L, ARNTL2, ERGIC2, TMTC1, DENND5B, and ETFBKMT as candidate genes for the neurodevelopmental disorder, and INTS13, REP15, PPFIBP1, and FAR2 as candidate genes for KS with ID. Notably, the high-level expression pattern of these genes in relevant human tissues further supported their candidacy. Based on our findings, we propose that dosage alterations of these candidate genes may contribute to sexual and/or cognitive impairments observed in patients with KS and/or ID. However, the confirmation of their causal roles necessitates further identification of point mutations in these candidate genes through next-generation sequencing.
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Affiliation(s)
- Afif Ben-Mahmoud
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Shotaro Kishikawa
- Gene Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
| | - Vijay Gupta
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Natalia T Leach
- Integrated Genetics, Laboratory Corporation of America Holdings, 3400 Computer Drive, Westborough, MA, 01581, USA
| | - Yiping Shen
- Division of Genetics and Genomics at Boston Children's Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Oana Moldovan
- Medical Genetics Service, Pediatric Department, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal
| | - Himanshu Goel
- Hunter Genetics, Waratah, NSW, 2298, Australia
- University of Newcastle, Callaghan, NSW, 2308, Australia
| | - Bruce Hopper
- Forster Genetics-Hunter New England Local Health District, Forster, NSW, 2428, Australia
| | - Kara Ranguin
- Department of Genetics, Reference Center for Rare Diseases of Developmental anomalies and polymalformative syndrome, CHU de Caen Normandie, Caen, France
| | - Nicolas Gruchy
- Department of Genetics, Reference Center for Rare Diseases of Developmental anomalies and polymalformative syndrome, CHU de Caen Normandie, Caen, France
| | - Saskia M Maas
- Department of Human Genetics, Amsterdam University Medical Center, Amsterdam, the Netherlands
- Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, the Netherlands
| | - Yves Lacassie
- Division of Genetics, Department of Pediatrics, Louisiana State University, New Orleans, LA, 70118, USA
| | - Soo-Hyun Kim
- Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK
| | - Woo-Yang Kim
- Department of Biological Sciences, Kent State University, Kent, OH, 44242, USA
| | - Bradley J Quade
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Cynthia C Morton
- Departments of Obstetrics and Gynecology and of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
- Manchester Centre for Audiology and Deafness, School of Health Sciences, University of Manchester, Manchester, UK
| | - Cheol-Hee Kim
- Department of Biology, Chungnam National University, Daejeon, 34134, Korea
| | - Lawrence C Layman
- Section of Reproductive Endocrinology, Infertility and Genetics, Department of Obstetrics and Gynecology, Augusta University, Augusta, GA, USA
- Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA, USA
| | - Hyung-Goo Kim
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar.
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
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32
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De Martino M, Pellecchia S, Esposito F, Liotti F, Credendino SC, Prevete N, Decaussin-Petrucci M, Chieffi P, De Vita G, Melillo RM, Fusco A, Pallante P. The lncRNA RMST is drastically downregulated in anaplastic thyroid carcinomas where exerts a tumor suppressor activity impairing epithelial-mesenchymal transition and stemness. Cell Death Discov 2023; 9:216. [PMID: 37393309 DOI: 10.1038/s41420-023-01514-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/12/2023] [Accepted: 06/21/2023] [Indexed: 07/03/2023] Open
Abstract
Thyroid cancer is the most prevalent endocrine malignancy and comprises a wide range of lesions subdivided into differentiated (DTC) and undifferentiated thyroid cancer (UTC), mainly represented by the anaplastic thyroid carcinoma (ATC). This is one of the most lethal malignancies in humankind leading invariably to patient death in few months. Then, a better comprehension of the mechanisms underlying the development of ATC is required to set up new therapeutic approaches. Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides in length that do not code for proteins. They show a strong regulatory function at both transcriptional and post-transcriptional level and are emerging as key players in regulating developmental processes. Their aberrant expression has been linked to several biological processes, including cancer, making them potential diagnostic and prognostic markers. We have recently analyzed the lncRNA expression profile in ATC through a microarray technique and have identified rhabdomyosarcoma 2-associated transcript (RMST) as one of the most downregulated lncRNA in ATC. RMST has been reported to be deregulated in a series of human cancers, to play an anti-oncogenic role in triple-negative breast cancer, and to modulate neurogenesis by interacting with SOX2. Therefore, these findings prompted us to investigate the role of RMST in ATC development. In this study we show that RMST levels are strongly decreased in ATC, but only slightly in DTC, indicating that the loss of this lncRNA could be related to the loss of the differentiation and high aggressiveness. We also report a concomitant increase of SOX2 levels in the same subset of ATC, that inversely correlated with RMST levels, further supporting the RMST/SOX2 relationship. Finally, functional studies demonstrate that the restoration of RMST in ATC cells reduces cell growth, migration and the stemness properties of ATC stem cells. In conclusion, these findings support a critical role of RMST downregulation in ATC development.
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Affiliation(s)
- Marco De Martino
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Via Pansini 5, 80131, Napoli, Italy
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania "Luigi Vanvitelli", Via De Crecchio 7, 80138, Napoli, Italy
| | - Simona Pellecchia
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Via Pansini 5, 80131, Napoli, Italy
| | - Francesco Esposito
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Via Pansini 5, 80131, Napoli, Italy
| | - Federica Liotti
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Via Pansini 5, 80131, Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli "Federico II", Via Pansini 5, 80131, Napoli, Italy
| | - Sara Carmela Credendino
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Via Pansini 5, 80131, Napoli, Italy
| | - Nella Prevete
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Via Pansini 5, 80131, Napoli, Italy
- Dipartimento di Scienze Mediche Traslazionali (DiSMeT), Università degli Studi di Napoli "Federico II", Via Pansini 5, 80131, Napoli, Italy
| | - Myriam Decaussin-Petrucci
- Service d'Anatomie et Cytologie Pathologiques, Centre de Biologie Sud, Groupement Hospitalier Lyon Sud, Universite Lyon 1, 69495, Pierre Bénite, France
| | - Paolo Chieffi
- Dipartimento di Medicina di Precisione, Università degli Studi della Campania "Luigi Vanvitelli", Via De Crecchio 7, 80138, Napoli, Italy
| | - Gabriella De Vita
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli "Federico II", Via Pansini 5, 80131, Napoli, Italy
| | - Rosa Marina Melillo
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Via Pansini 5, 80131, Napoli, Italy
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli "Federico II", Via Pansini 5, 80131, Napoli, Italy
| | - Alfredo Fusco
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Via Pansini 5, 80131, Napoli, Italy.
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche (DMMBM), Università degli Studi di Napoli "Federico II", Via Pansini 5, 80131, Napoli, Italy.
- Instituto Nacional de Cancer, 37908, Laboratorio de Carcinogênese Molecular, Rua Andre Cavalcanti 37, Centro, 20231-050, Rio de Janeiro, Brazil.
| | - Pierlorenzo Pallante
- Istituto per l'Endocrinologia e l'Oncologia Sperimentale (IEOS) "G. Salvatore", Consiglio Nazionale delle Ricerche (CNR), Via Pansini 5, 80131, Napoli, Italy.
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Tokunaga M, Imamura T. Emerging concepts involving inhibitory and activating RNA functionalization towards the understanding of microcephaly phenotypes and brain diseases in humans. Front Cell Dev Biol 2023; 11:1168072. [PMID: 37408531 PMCID: PMC10318543 DOI: 10.3389/fcell.2023.1168072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 06/12/2023] [Indexed: 07/07/2023] Open
Abstract
Microcephaly is characterized as a small head circumference, and is often accompanied by developmental disorders. Several candidate risk genes for this disease have been described, and mutations in non-coding regions are occasionally found in patients with microcephaly. Various non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), SINEUPs, telomerase RNA component (TERC), and promoter-associated lncRNAs (pancRNAs) are now being characterized. These ncRNAs regulate gene expression, enzyme activity, telomere length, and chromatin structure through RNA binding proteins (RBPs)-RNA interaction. Elucidating the potential roles of ncRNA-protein coordination in microcephaly pathogenesis might contribute to its prevention or recovery. Here, we introduce several syndromes whose clinical features include microcephaly. In particular, we focus on syndromes for which ncRNAs or genes that interact with ncRNAs may play roles. We discuss the possibility that the huge ncRNA field will provide possible new therapeutic approaches for microcephaly and also reveal clues about the factors enabling the evolutionary acquisition of the human-specific "large brain."
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34
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Mattick JS, Amaral PP, Carninci P, Carpenter S, Chang HY, Chen LL, Chen R, Dean C, Dinger ME, Fitzgerald KA, Gingeras TR, Guttman M, Hirose T, Huarte M, Johnson R, Kanduri C, Kapranov P, Lawrence JB, Lee JT, Mendell JT, Mercer TR, Moore KJ, Nakagawa S, Rinn JL, Spector DL, Ulitsky I, Wan Y, Wilusz JE, Wu M. Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat Rev Mol Cell Biol 2023; 24:430-447. [PMID: 36596869 PMCID: PMC10213152 DOI: 10.1038/s41580-022-00566-8] [Citation(s) in RCA: 948] [Impact Index Per Article: 474.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2022] [Indexed: 01/05/2023]
Abstract
Genes specifying long non-coding RNAs (lncRNAs) occupy a large fraction of the genomes of complex organisms. The term 'lncRNAs' encompasses RNA polymerase I (Pol I), Pol II and Pol III transcribed RNAs, and RNAs from processed introns. The various functions of lncRNAs and their many isoforms and interleaved relationships with other genes make lncRNA classification and annotation difficult. Most lncRNAs evolve more rapidly than protein-coding sequences, are cell type specific and regulate many aspects of cell differentiation and development and other physiological processes. Many lncRNAs associate with chromatin-modifying complexes, are transcribed from enhancers and nucleate phase separation of nuclear condensates and domains, indicating an intimate link between lncRNA expression and the spatial control of gene expression during development. lncRNAs also have important roles in the cytoplasm and beyond, including in the regulation of translation, metabolism and signalling. lncRNAs often have a modular structure and are rich in repeats, which are increasingly being shown to be relevant to their function. In this Consensus Statement, we address the definition and nomenclature of lncRNAs and their conservation, expression, phenotypic visibility, structure and functions. We also discuss research challenges and provide recommendations to advance the understanding of the roles of lncRNAs in development, cell biology and disease.
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Affiliation(s)
- John S Mattick
- School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW, Australia.
- UNSW RNA Institute, UNSW, Sydney, NSW, Australia.
| | - Paulo P Amaral
- INSPER Institute of Education and Research, São Paulo, Brazil
| | - Piero Carninci
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Human Technopole, Milan, Italy
| | - Susan Carpenter
- Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, USA
| | - Howard Y Chang
- Center for Personal Dynamics Regulomes, Stanford University School of Medicine, Stanford, CA, USA
- Department of Dermatology, Stanford, CA, USA
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Ling-Ling Chen
- CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
| | - Runsheng Chen
- Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Caroline Dean
- John Innes Centre, Norwich Research Park, Norwich, UK
| | - Marcel E Dinger
- School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW, Australia
- UNSW RNA Institute, UNSW, Sydney, NSW, Australia
| | - Katherine A Fitzgerald
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | | | - Mitchell Guttman
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
| | - Tetsuro Hirose
- Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
| | - Maite Huarte
- Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
- Institute of Health Research of Navarra, Pamplona, Spain
| | - Rory Johnson
- School of Biology and Environmental Science, University College Dublin, Dublin, Ireland
- Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Chandrasekhar Kanduri
- Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Philipp Kapranov
- Institute of Genomics, School of Medicine, Huaqiao University, Xiamen, China
| | - Jeanne B Lawrence
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Joshua T Mendell
- Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX, USA
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA
| | - Timothy R Mercer
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia
| | - Kathryn J Moore
- Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Shinichi Nakagawa
- RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
| | - John L Rinn
- Department of Biochemistry, University of Colorado Boulder, Boulder, CO, USA
- BioFrontiers Institute, University of Colorado Boulder, Boulder, CO, USA
- Howard Hughes Medical Institute, University of Colorado Boulder, Boulder, CO, USA
| | - David L Spector
- Cold Spring Harbour Laboratory, Cold Spring Harbour, NY, USA
| | - Igor Ulitsky
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Yue Wan
- Laboratory of RNA Genomics and Structure, Genome Institute of Singapore, A*STAR, Singapore, Singapore
- Department of Biochemistry, National University of Singapore, Singapore, Singapore
| | - Jeremy E Wilusz
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX, USA
| | - Mian Wu
- Translational Research Institute, Henan Provincial People's Hospital, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
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Spirito L, Maturi R, Credendino SC, Manfredi C, Arcaniolo D, De Martino M, Esposito F, Napolitano L, Di Bello F, Fusco A, Pallante P, De Sio M, De Vita G. Differential Expression of LncRNA in Bladder Cancer Development. Diagnostics (Basel) 2023; 13:diagnostics13101745. [PMID: 37238229 DOI: 10.3390/diagnostics13101745] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/05/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Bladder cancer (BC) is the tenth most common cancer, with urothelial carcinoma representing about 90% of all BC, including neoplasms and carcinomas of different grades of malignancy. Urinary cytology has a significant role in BC screening and surveillance, although it has a low detection rate and high dependence on the pathologist's experience. The currently available biomarkers are not implemented into routine clinical practice due to high costs or low sensitivity. In recent years, the role of lncRNAs in BC has emerged, even though it is still poorly explored. We have previously shown that the lncRNAs Metallophosphoesterase Domain-Containing 2 Antisense RNA 1 (MPPED2-AS1), Rhabdomyosarcoma-2 Associated Transcript (RMST), Kelch-like protein 14 antisense (Klhl14AS) and Prader Willi/Angelman region RNA 5 (PAR5) are involved in the progression of different types of cancers. Here, we investigated the expression of these molecules in BC, first by interrogating the GEPIA database and observing a different distribution of expression levels between normal and cancer specimens. We then measured them in a cohort of neoplastic bladder lesions, either benign or malignant, from patients with suspicion of BC undergoing transurethral resection of bladder tumor (TURBT). The total RNA from biopsies was analyzed using qRT-PCR for the expression of the four lncRNA genes, showing differential expression of the investigated lncRNAs between normal tissue, benign lesions and cancers. In conclusion, the data reported here highlight the involvement of novel lncRNAs in BC development, whose altered expression could potentially affect the regulatory circuits in which these molecules are involved. Our study paves the way for testing lncRNA genes as markers for BC diagnosis and/or follow-up.
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Affiliation(s)
- Lorenzo Spirito
- Urology Unit, Department of Woman Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via De Crecchio 7, 80138 Naples, Italy
| | - Rufina Maturi
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Sara Carmela Credendino
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Celeste Manfredi
- Urology Unit, Department of Woman Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via De Crecchio 7, 80138 Naples, Italy
| | - Davide Arcaniolo
- Urology Unit, Department of Woman Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via De Crecchio 7, 80138 Naples, Italy
| | - Marco De Martino
- Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), Via Pansini, 5, 80131 Naples, Italy
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via De Crecchio 7, 80138 Napoli, Italy
| | - Francesco Esposito
- Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), Via Pansini, 5, 80131 Naples, Italy
| | - Luigi Napolitano
- Urology Unit, Department of Neurosciences, Reproductive Sciences, and Odontostomatology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Francesco Di Bello
- Urology Unit, Department of Neurosciences, Reproductive Sciences, and Odontostomatology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
| | - Alfredo Fusco
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
- Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), Via Pansini, 5, 80131 Naples, Italy
| | - Pierlorenzo Pallante
- Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Research Council (CNR), Via Pansini, 5, 80131 Naples, Italy
| | - Marco De Sio
- Urology Unit, Department of Woman Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Via De Crecchio 7, 80138 Naples, Italy
| | - Gabriella De Vita
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via Pansini 5, 80131 Naples, Italy
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36
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Sherazi SAM, Abbasi A, Jamil A, Uzair M, Ikram A, Qamar S, Olamide AA, Arshad M, Fried PJ, Ljubisavljevic M, Wang R, Bashir S. Molecular hallmarks of long non-coding RNAs in aging and its significant effect on aging-associated diseases. Neural Regen Res 2023; 18:959-968. [PMID: 36254975 PMCID: PMC9827784 DOI: 10.4103/1673-5374.355751] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 06/23/2022] [Accepted: 08/08/2022] [Indexed: 01/11/2023] Open
Abstract
Aging is linked to the deterioration of many physical and cognitive abilities and is the leading risk factor for Alzheimer's disease. The growing aging population is a significant healthcare problem globally that researchers must investigate to better understand the underlying aging processes. Advances in microarrays and sequencing techniques have resulted in deeper analyses of diverse essential genomes (e.g., mouse, human, and rat) and their corresponding cell types, their organ-specific transcriptomes, and the tissue involved in aging. Traditional gene controllers such as DNA- and RNA-binding proteins significantly influence such programs, causing the need to sort out long non-coding RNAs, a new class of powerful gene regulatory elements. However, their functional significance in the aging process and senescence has yet to be investigated and identified. Several recent researchers have associated the initiation and development of senescence and aging in mammals with several well-reported and novel long non-coding RNAs. In this review article, we identified and analyzed the evolving functions of long non-coding RNAs in cellular processes, including cellular senescence, aging, and age-related pathogenesis, which are the major hallmarks of long non-coding RNAs in aging.
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Affiliation(s)
- Syed Aoun Mehmood Sherazi
- Department of Biological Sciences, Faculty of Basic & Applied Sciences, International Islamic University, Islamabad, Pakistan
| | - Asim Abbasi
- Department of Biological Sciences, University of Arkansas, Fayetteville, AR, USA
| | - Abdullah Jamil
- Department of Pharmacology, Government College University, Faisalabad, Pakistan
| | - Mohammad Uzair
- Department of Biological Sciences, Faculty of Basic & Applied Sciences, International Islamic University, Islamabad, Pakistan
| | - Ayesha Ikram
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Shanzay Qamar
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | | | - Muhammad Arshad
- Department of Biological Sciences, Faculty of Basic & Applied Sciences, International Islamic University, Islamabad, Pakistan
| | - Peter J. Fried
- Department of Neurology, Berenson-Allen Center for Noninvasive Brain Stimulation and Division of Cognitive Neurology, Beth Israel Deaconess Medical Center (KS 158), Harvard Medical School, Boston, MA, USA
| | - Milos Ljubisavljevic
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Ran Wang
- Department of Psychiatry, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
- Mental Health Institute of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Shahid Bashir
- Neuroscience Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia
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Du J, Li Y, Su Y, Zhi W, Zhang J, Zhang C, Wang J, Deng W, Zhao S. LncRNA Pnky Positively Regulates Neural Stem Cell Migration by Modulating mRNA Splicing and Export of Target Genes. Cell Mol Neurobiol 2023; 43:1199-1218. [PMID: 35748966 PMCID: PMC11414454 DOI: 10.1007/s10571-022-01241-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 06/06/2022] [Indexed: 11/28/2022]
Abstract
Directed migration of neural stem cells (NSCs) is critical for embryonic neurogenesis and the healing of neurological injuries. The long noncoding RNA (lncRNA) Pnky has been reported to regulate neuronal differentiation of NSCs by interacting with PTBP1. However, its regulatory effect on NSC migration remains to be determined. Herein, we identified that Pnky is also a key regulator of NSC migration in mice, as underscored by the finding that Pnky silencing suppressed but Pnky overexpression promoted the in vitro migration of both C17.2 and NE4C murine NSCs. Additionally, in vivo cell tracking demonstrated that Pnky depletion attenuated but Pnky overexpression facilitated the migration of NE4C cells in the spinal canal after transplantation via injection into the spinal canal. Mechanistically, Pnky regulated the expression of a core set of critical regulators that direct NSC migration, including MMP2, MMP9, Connexin43, Paxillin, AKT, ERK, and P38MAPK. Using catRAPID, a web server for large-scale prediction of protein-RNA interactions, the splicing factors U2AF1 and U2AF1L4, as well as the mRNA export adaptors SARNP, Aly/Ref, and THOC7, were predicted to interact strongly with Pnky. Further investigations using colocalization and RNA immunoprecipitation (RIP) assays confirmed the direct binding of Pnky to U2AF1, SARNP, Aly/Ref, and THOC7. Transcriptomic profiling revealed that as many as 5319 differential splicing events of 3848 genes, which were highly enriched in focal adhesion, PI3K-Akt and MAPK signaling pathways, were affected by Pnky depletion. The predominant subtype of differential splicing by Pnky depletion is intron retention, followed by alternative 5' and 3' splice sites and mutually exclusive exons. Moreover, Pnky knockdown substantially blocked but Pnky overexpression facilitated the export of MMP2, Paxillin, AKT, p38MAPK, and other mRNAs to the cytosol. Collectively, our data showed that through interacting with U2AF1, SARNP, Aly/Ref, and THOC7, Pnky couples and modulates the splicing and export of target mRNAs, which consequently controlling NSC migration. These findings provide a possible theoretical basis of NSC migration regulation.
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Affiliation(s)
- Jiannan Du
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei, 430065, People's Republic of China
| | - Yuan Li
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei, 430065, People's Republic of China
| | - Yuting Su
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei, 430065, People's Republic of China
| | - Wenqian Zhi
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei, 430065, People's Republic of China
| | - Jiale Zhang
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei, 430065, People's Republic of China
| | - Cheng Zhang
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei, 430065, People's Republic of China
| | - Juan Wang
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei, 430065, People's Republic of China
| | - Wensheng Deng
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei, 430065, People's Republic of China.
| | - Shasha Zhao
- College of Life Science and Health, Wuhan University of Science and Technology, Wuhan, Hubei, 430065, People's Republic of China.
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Ben-Mahmoud A, Kishikawa S, Gupta V, Leach NT, Shen Y, Moldovan O, Goel H, Hopper B, Ranguin K, Gruchy N, Maas SM, Lacassie Y, Kim SH, Kim WY, Quade BJ, Morton CC, Kim CH, Layman LC, Kim HG. A microdeletion del(12)(p11.21p11.23) with a cryptic unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome. RESEARCH SQUARE 2023:rs.3.rs-2572736. [PMID: 37034680 PMCID: PMC10081357 DOI: 10.21203/rs.3.rs-2572736/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
Abstract
In an apparently balanced translocation t(7;12)(q22;q24)dn exhibiting both Kallmann syndrome (KS) and intellectual disability (ID), we detected a cryptic heterozygous 4.7 Mb del(12)(p11.21p11.23) unrelated to the translocation breakpoint. This new finding raised the possibility that KS combined with neurological disorder in this patient could be caused by gene(s) within this deletion at 12p11.21-12p11.23 instead of disrupted or dysregulated genes at the genomic breakpoints. Screening of five candidate genes at both breakpoints in 48 KS patients we recruited found no mutation, corroborating our supposition. To substantiate this hypothesis further, we recruited six additional subjects with small CNVs and analyzed eight individuals carrying small CNVs in this region from DECIPHER to dissect 12p11.21-12p11.23. We used multiple complementary approaches including a phenotypic-genotypic comparison of reported cases, a review of knockout animal models recapitulating the human phenotypes, and analyses of reported variants in the interacting genes with corresponding phenotypes. The results identified one potential KS candidate gene ( TSPAN11 ), seven candidate genes for the neurodevelopmental disorder ( TM7SF3 , STK38L , ARNTL2 , ERGIC2 , TMTC1 , DENND5B , and ETFBKMT ), and four candidate genes for KS with ID ( INTS13 , REP15 , PPFIBP1 , and FAR2 ). The high-level expression pattern in the relevant human tissues further suggested the candidacy of these genes. We propose that the dosage alterations of the candidate genes may contribute to sexual and/or cognitive impairment in patients with KS and/or ID. Further identification of point mutations through next generation sequencing will be necessary to confirm their causal roles.
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Affiliation(s)
| | | | | | | | | | - Oana Moldovan
- Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte
| | | | - Bruce Hopper
- Forster Genetics-Hunter New England Local Health District
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Espadas I, Wingfield J, Grinman E, Ghosh I, Chanda K, Nakahata Y, Bauer K, Raveendra B, Kiebler M, Yasuda R, Rangaraju V, Puthanveettil S. SLAMR, a synaptically targeted lncRNA, facilitates the consolidation of contextual fear memory. RESEARCH SQUARE 2023:rs.3.rs-2489387. [PMID: 36993323 PMCID: PMC10055528 DOI: 10.21203/rs.3.rs-2489387/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/19/2023]
Abstract
LncRNAs are involved in critical processes for cell homeostasis and function. However, it remains largely unknown whether and how the transcriptional regulation of long noncoding RNAs results in activity-dependent changes at the synapse and facilitate formation of long-term memories. Here, we report the identification of a novel lncRNA, SLAMR, that becomes enriched in CA1- but not in CA3-hippocampal neurons upon contextual fear conditioning. SLAMR is transported to dendrites via the molecular motor KIF5C and recruited to the synapse in response to stimulation. Loss of function of SLAMR reduced dendritic complexity and impaired activity dependent changes in spine structural plasticity. Interestingly, gain of function of SLAMR enhanced dendritic complexity, and spine density through enhanced translation. Analyses of the SLAMR interactome revealed its association with CaMKIIα protein through a 220-nucleotide element and its modulation of CaMKIIα activity. Furthermore, loss-of-function of SLAMR in CA1 selectively impairs consolidation but neither acquisition, recall, nor extinction of fear memory and spatial memory. Together, these results establish a new mechanism for activity dependent changes at the synapse and consolidation of contextual fear.
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Affiliation(s)
- Isabel Espadas
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Jenna Wingfield
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Eddie Grinman
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Ilika Ghosh
- Max Planck Florida Institute, Jupiter, FL, USA
| | - Kaushik Chanda
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | | | - Karl Bauer
- Biomedical Center (BMC), Department for Cell Biology, Medical Faculty, Ludwig-Maximilians-University of Munich, 82152 Planegg-Martinsried, Germany
| | - Bindu Raveendra
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
| | - Michael Kiebler
- Biomedical Center (BMC), Department for Cell Biology, Medical Faculty, Ludwig-Maximilians-University of Munich, 82152 Planegg-Martinsried, Germany
| | | | | | - Sathyanarayanan Puthanveettil
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL, USA
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40
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Seeler S, Andersen MS, Sztanka-Toth T, Rybiczka-Tešulov M, van den Munkhof MH, Chang CC, Maimaitili M, Venø MT, Hansen TB, Pasterkamp RJ, Rybak-Wolf A, Denham M, Rajewsky N, Kristensen LS, Kjems J. A Circular RNA Expressed from the FAT3 Locus Regulates Neural Development. Mol Neurobiol 2023; 60:3239-3260. [PMID: 36840844 PMCID: PMC10122638 DOI: 10.1007/s12035-023-03253-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 01/28/2023] [Indexed: 02/26/2023]
Abstract
Circular RNAs (circRNAs) are key regulators of cellular processes, are abundant in the nervous system, and have putative regulatory roles during neural differentiation. However, the knowledge about circRNA functions in brain development is limited. Here, using RNA-sequencing, we show that circRNA levels increased substantially over the course of differentiation of human embryonic stem cells into rostral and caudal neural progenitor cells (NPCs), including three of the most abundant circRNAs, ciRS-7, circRMST, and circFAT3. Knockdown of circFAT3 during early neural differentiation resulted in minor transcriptional alterations in bulk RNA analysis. However, single-cell transcriptomics of 30 and 90 days differentiated cerebral organoids deficient in circFAT3 showed a loss of telencephalic radial glial cells and mature cortical neurons, respectively. Furthermore, non-telencephalic NPCs in cerebral organoids showed changes in the expression of genes involved in neural differentiation and migration, including FAT4, ERBB4, UNC5C, and DCC. In vivo depletion of circFat3 in mouse prefrontal cortex using in utero electroporation led to alterations in the positioning of the electroporated cells within the neocortex. Overall, these findings suggest a conserved role for circFAT3 in neural development involving the formation of anterior cell types, neuronal differentiation, or migration.
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Affiliation(s)
- Sabine Seeler
- Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Aarhus, Denmark
- Department of Biomedicine, The Skou Building, Aarhus University, 8000 Aarhus C, Aarhus, Denmark
| | - Maria Schertz Andersen
- Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Aarhus, Denmark
| | - Tamas Sztanka-Toth
- Berlin Institute for Medical Systems Biology (BIMSB), MDC Berlin-Mitte, 10115, Berlin, Germany
| | - Mateja Rybiczka-Tešulov
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, 3584 CG, Utrecht, Netherlands
| | - Marleen H van den Munkhof
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, 3584 CG, Utrecht, Netherlands
| | - Chi-Chih Chang
- Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Aarhus, Denmark
| | - Muyesier Maimaitili
- Department of Biomedicine, The Skou Building, Aarhus University, 8000 Aarhus C, Aarhus, Denmark
- Danish Research Institute of Translational Neuroscience, Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000 Aarhus C, Aarhus, Denmark
| | - Morten Trillingsgaard Venø
- Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Aarhus, Denmark
- Omiics ApS, 8200 Aarhus N, Aarhus, Denmark
| | - Thomas Birkballe Hansen
- Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Aarhus, Denmark
| | - R Jeroen Pasterkamp
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, 3584 CG, Utrecht, Netherlands
| | - Agnieszka Rybak-Wolf
- Berlin Institute for Medical Systems Biology (BIMSB), MDC Berlin-Mitte, 10115, Berlin, Germany
| | - Mark Denham
- Department of Biomedicine, The Skou Building, Aarhus University, 8000 Aarhus C, Aarhus, Denmark
- Danish Research Institute of Translational Neuroscience, Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000 Aarhus C, Aarhus, Denmark
| | - Nikolaus Rajewsky
- Berlin Institute for Medical Systems Biology (BIMSB), MDC Berlin-Mitte, 10115, Berlin, Germany
| | - Lasse Sommer Kristensen
- Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Aarhus, Denmark.
- Department of Biomedicine, The Skou Building, Aarhus University, 8000 Aarhus C, Aarhus, Denmark.
| | - Jørgen Kjems
- Interdisciplinary Nanoscience Center, Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Aarhus, Denmark.
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Tan Z, Li W, Cheng X, Zhu Q, Zhang X. Non-Coding RNAs in the Regulation of Hippocampal Neurogenesis and Potential Treatment Targets for Related Disorders. Biomolecules 2022; 13:biom13010018. [PMID: 36671403 PMCID: PMC9855933 DOI: 10.3390/biom13010018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/17/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
Non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, circRNAs, and piRNAs, do not encode proteins. Nonetheless, they have critical roles in a variety of cellular activities-such as development, neurogenesis, degeneration, and the response to injury to the nervous system-via protein translation, RNA splicing, gene activation, silencing, modifications, and editing; thus, they may serve as potential targets for disease treatment. The activity of adult neural stem cells (NSCs) in the subgranular zone of the hippocampal dentate gyrus critically influences hippocampal function, including learning, memory, and emotion. ncRNAs have been shown to be involved in the regulation of hippocampal neurogenesis, including proliferation, differentiation, and migration of NSCs and synapse formation. The interaction among ncRNAs is complex and diverse and has become a major topic within the life science. This review outlines advances in research on the roles of ncRNAs in modulating NSC bioactivity in the hippocampus and discusses their potential applications in the treatment of illnesses affecting the hippocampus.
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Affiliation(s)
- Zhengye Tan
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
| | - Wen Li
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
| | - Xiang Cheng
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
| | - Qing Zhu
- School of Pharmacy, Nantong University, Nantong 226001, China
- Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, Nantong 226001, China
| | - Xinhua Zhang
- Department of Anatomy, Institute of Neurobiology, Medical School, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China
- Central Lab, Yancheng Third People’s Hospital, The Sixth Affiliated Hospital of Nantong University, Yancheng 224001, China
- Correspondence:
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42
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Akter M, Ding B. Modeling Movement Disorders via Generation of hiPSC-Derived Motor Neurons. Cells 2022; 11:3796. [PMID: 36497056 PMCID: PMC9737271 DOI: 10.3390/cells11233796] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 11/19/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022] Open
Abstract
Generation of motor neurons (MNs) from human-induced pluripotent stem cells (hiPSCs) overcomes the limited access to human brain tissues and provides an unprecedent approach for modeling MN-related diseases. In this review, we discuss the recent progression in understanding the regulatory mechanisms of MN differentiation and their applications in the generation of MNs from hiPSCs, with a particular focus on two approaches: induction by small molecules and induction by lentiviral delivery of transcription factors. At each induction stage, different culture media and supplements, typical growth conditions and cellular morphology, and specific markers for validation of cell identity and quality control are specifically discussed. Both approaches can generate functional MNs. Currently, the major challenges in modeling neurological diseases using iPSC-derived neurons are: obtaining neurons with high purity and yield; long-term neuron culture to reach full maturation; and how to culture neurons more physiologically to maximize relevance to in vivo conditions.
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Affiliation(s)
| | - Baojin Ding
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA
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43
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Identification of PAX6 and NFAT4 as the Transcriptional Regulators of the Long Noncoding RNA Mrhl in Neuronal Progenitors. Mol Cell Biol 2022; 42:e0003622. [PMID: 36317923 PMCID: PMC9670966 DOI: 10.1128/mcb.00036-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The long noncoding RNA (lncRNA) Mrhl has been shown to be involved in coordinating meiotic commitment of mouse spermatogonial progenitors and differentiation events in mouse embryonic stem cells. Here, we characterized the interplay of Mrhl with lineage-specific transcription factors during mouse neuronal lineage development. Our results demonstrate that Mrhl is expressed in the neuronal progenitor populations in mouse embryonic brains and in retinoic acid-derived radial-glia-like neuronal progenitor cells. Depletion of Mrhl leads to early differentiation of neuronal progenitors to a more committed state. A master transcription factor, PAX6, directly binds to the Mrhl promoter at a major site in the distal promoter, located at 2.9 kb upstream of the transcription start site (TSS) of Mrhl. Furthermore, NFAT4 occupies the Mrhl-proximal promoter at two sites, at 437 base pairs (bp) and 143 bp upstream of the TSS. Independent knockdown studies for PAX6 and NFAT4 confirm that they regulate Mrhl expression in neuronal progenitors. We also show that PAX6 and NFAT4 associate with each other in the same chromatin complex. NFAT4 occupies the Mrhl promoter in PAX6-bound chromatin, implying possible coregulation of Mrhl. Our studies are crucial for understanding how lncRNAs are regulated by major lineage-specific transcription factors, in order to define specific development and differentiation events.
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44
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Borgenheimer E, Hamel K, Sheeler C, Moncada FL, Sbrocco K, Zhang Y, Cvetanovic M. Single nuclei RNA sequencing investigation of the Purkinje cell and glial changes in the cerebellum of transgenic Spinocerebellar ataxia type 1 mice. Front Cell Neurosci 2022; 16:998408. [PMID: 36457352 PMCID: PMC9706545 DOI: 10.3389/fncel.2022.998408] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 10/27/2022] [Indexed: 11/16/2022] Open
Abstract
Glial cells constitute half the population of the human brain and are essential for normal brain function. Most, if not all, brain diseases are characterized by reactive gliosis, a process by which glial cells respond and contribute to neuronal pathology. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease characterized by a severe degeneration of cerebellar Purkinje cells (PCs) and cerebellar gliosis. SCA1 is caused by an abnormal expansion of CAG repeats in the gene Ataxin1 (ATXN1). While several studies reported the effects of mutant ATXN1 in Purkinje cells, it remains unclear how cerebellar glia respond to dysfunctional Purkinje cells in SCA1. To address this question, we performed single nuclei RNA sequencing (snRNA seq) on cerebella of early stage Pcp2-ATXN1[82Q] mice, a transgenic SCA1 mouse model expressing mutant ATXN1 only in Purkinje cells. We found no changes in neuronal and glial proportions in the SCA1 cerebellum at this early disease stage compared to wild-type controls. Importantly, we observed profound non-cell autonomous and potentially neuroprotective reactive gene and pathway alterations in Bergmann glia, velate astrocytes, and oligodendrocytes in response to Purkinje cell dysfunction.
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Affiliation(s)
- Ella Borgenheimer
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States
| | - Katherine Hamel
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States
| | - Carrie Sheeler
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States
| | | | - Kaelin Sbrocco
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States
| | - Ying Zhang
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States
- Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, United States
| | - Marija Cvetanovic
- Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States
- Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, United States
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45
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Huang J, Jiang B, Li GW, Zheng D, Li M, Xie X, Pan Y, Wei M, Liu X, Jiang X, Zhang X, Yang L, Bao L, Wang B. m6A-modified lincRNA Dubr is required for neuronal development by stabilizing YTHDF1/3 and facilitating mRNA translation. Cell Rep 2022; 41:111693. [DOI: 10.1016/j.celrep.2022.111693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 09/16/2022] [Accepted: 10/31/2022] [Indexed: 11/23/2022] Open
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46
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jiayang G, Xin G, chunxia Y, Xiaojuan G, Pan M, Shanzhi G, Bao Z. Transcriptome-wide association study by different approaches reveals candidate causal genes for cannabis use disorder. Gene 2022; 851:147048. [DOI: 10.1016/j.gene.2022.147048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 10/27/2022] [Accepted: 11/08/2022] [Indexed: 11/14/2022]
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47
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Schneider MF, Müller V, Müller SA, Lichtenthaler SF, Becker PB, Scheuermann JC. LncRNA RUS shapes the gene expression program towards neurogenesis. Life Sci Alliance 2022; 5:5/10/e202201504. [PMID: 35688487 PMCID: PMC9187872 DOI: 10.26508/lsa.202201504] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/13/2022] [Accepted: 05/13/2022] [Indexed: 11/29/2022] Open
Abstract
The chromatin-associated lncRNA RUS binds in the vicinity to neural differentiation-associated genes and regulates them in a context-dependent manner to enable proper neuron development. The evolution of brain complexity correlates with an increased expression of long, noncoding (lnc) RNAs in neural tissues. Although prominent examples illustrate the potential of lncRNAs to scaffold and target epigenetic regulators to chromatin loci, only few cases have been described to function during brain development. We present a first functional characterization of the lncRNA LINC01322, which we term RUS for “RNA upstream of Slitrk3.” The RUS gene is well conserved in mammals by sequence and synteny next to the neurodevelopmental gene Slitrk3. RUS is exclusively expressed in neural cells and its expression increases during neuronal differentiation of mouse embryonic cortical neural stem cells. Depletion of RUS locks neuronal precursors in an intermediate state towards neuronal differentiation resulting in arrested cell cycle and increased apoptosis. RUS associates with chromatin in the vicinity of genes involved in neurogenesis, most of which change their expression upon RUS depletion. The identification of a range of epigenetic regulators as specific RUS interactors suggests that the lncRNA may mediate gene activation and repression in a highly context-dependent manner.
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Affiliation(s)
- Marius F Schneider
- Division of Molecular Biology, Biomedical Center Munich, Ludwig-Maximilians-University, Munich, Germany.,Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center Munich (BMC), Ludwig-Maximilians-Universität München, Munich, Germany
| | - Veronika Müller
- Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center Munich (BMC), Ludwig-Maximilians-Universität München, Munich, Germany
| | - Stephan A Müller
- Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.,German Center for Neurodegenerative Diseases (DZNE) Munich and Neuroproteomics Unit, Technical University, Munich, Germany
| | - Stefan F Lichtenthaler
- Neuroproteomics, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.,German Center for Neurodegenerative Diseases (DZNE) Munich and Neuroproteomics Unit, Technical University, Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Peter B Becker
- Division of Molecular Biology, Biomedical Center Munich, Ludwig-Maximilians-University, Munich, Germany
| | - Johanna C Scheuermann
- Division of Metabolic Biochemistry, Faculty of Medicine, Biomedical Center Munich (BMC), Ludwig-Maximilians-Universität München, Munich, Germany
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48
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Wu Y, Wang Z, Yu S, Liu D, Sun L. LncmiRHG-MIR100HG: A new budding star in cancer. Front Oncol 2022; 12:997532. [PMID: 36212400 PMCID: PMC9544809 DOI: 10.3389/fonc.2022.997532] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 09/12/2022] [Indexed: 11/24/2022] Open
Abstract
MIR100HG, also known as lncRNA mir-100-let-7a-2-mir-125b-1 cluster host gene, is a new and critical regulator in cancers in recent years. MIR100HG is dysregulated in various cancers and plays an oncogenic or tumor-suppressive role, which participates in many tumor cell biology processes and cancer-related pathways. The errant expression of MIR100HG has inspired people to investigate the function of MIR100HG and its diagnostic and therapeutic potential in cancers. Many studies have indicated that dysregulated expression of MIR100HG is markedly correlated with poor prognosis and clinicopathological features. In this review, we will highlight the characteristics and introduce the role of MIR100HG in different cancers, and summarize the molecular mechanism, pathways, chemoresistance, and current research progress of MIR100HG in cancers. Furthermore, some open questions in this rapidly advancing field are proposed. These updates clarify our understanding of MIR100HG in cancers, which may pave the way for the application of MIR100HG-targeting approaches in future cancer diagnosis, prognosis, and therapy.
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Affiliation(s)
- Yingnan Wu
- Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Zhenzhen Wang
- Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, China
| | - Shan Yu
- Department of Pathology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Dongzhe Liu
- Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University Health Science Center, Shenzhen, China
| | - Litao Sun
- Cancer Center, Department of Ultrasound Medicine, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital of Hangzhou Medical College, Hangzhou, China
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49
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Parmentier T, James FMK, Hewitson E, Bailey C, Werry N, Sheridan SD, Perlis RH, Perreault ML, Gaitero L, Lalonde J, LaMarre J. Human cerebral spheroids undergo 4-aminopyridine-induced, activity associated changes in cellular composition and microrna expression. Sci Rep 2022; 12:9143. [PMID: 35650420 PMCID: PMC9160269 DOI: 10.1038/s41598-022-13071-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 05/20/2022] [Indexed: 01/03/2023] Open
Abstract
Activity-induced neurogenesis has been extensively studied in rodents but the lack of ante mortem accessibility to human brain at the cellular and molecular levels limits studies of the process in humans. Using cerebral spheroids derived from human induced pluripotent stem cells (iPSCs), we investigated the effects of 4-aminopyridine (4AP) on neuronal activity and associated neurogenesis. Our studies demonstrate that 4AP increases neuronal activity in 3-month-old cerebral spheroids while increasing numbers of new neurons and decreasing the population of new glial cells. We also observed a significant decrease in the expression of miR-135a, which has previously been shown to be decreased in exercise-induced neurogenesis. Predicted targets of miR-135a include key participants in the SMAD2/3 and BDNF pathways. Together, our results suggest that iPSC-derived cerebral spheroids are an attractive model to study several aspects of activity-induced neurogenesis.
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Affiliation(s)
- Thomas Parmentier
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.,Département de Sciences Cliniques, Faculté de Médecine Vétérinaire, Université de Montréal, Montréal, QC, Canada
| | - Fiona M K James
- Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Elizabeth Hewitson
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Craig Bailey
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Nicholas Werry
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Steven D Sheridan
- Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.,Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - Roy H Perlis
- Center for Quantitative Health, Center for Genomic Medicine and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.,Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - Melissa L Perreault
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Luis Gaitero
- Department of Clinical Studies, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
| | - Jasmin Lalonde
- Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph, Guelph, ON, Canada
| | - Jonathan LaMarre
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada.
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50
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The Emerging Roles of Long Non-Coding RNAs in Intellectual Disability and Related Neurodevelopmental Disorders. Int J Mol Sci 2022; 23:ijms23116118. [PMID: 35682796 PMCID: PMC9181295 DOI: 10.3390/ijms23116118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/23/2022] [Accepted: 05/27/2022] [Indexed: 02/05/2023] Open
Abstract
In the human brain, long non-coding RNAs (lncRNAs) are widely expressed in an exquisitely temporally and spatially regulated manner, thus suggesting their contribution to normal brain development and their probable involvement in the molecular pathology of neurodevelopmental disorders (NDD). Bypassing the classic protein-centric conception of disease mechanisms, some studies have been conducted to identify and characterize the putative roles of non-coding sequences in the genetic pathogenesis and diagnosis of complex diseases. However, their involvement in NDD, and more specifically in intellectual disability (ID), is still poorly documented and only a few genomic alterations affecting the lncRNAs function and/or expression have been causally linked to the disease endophenotype. Considering that a significant fraction of patients still lacks a genetic or molecular explanation, we expect that a deeper investigation of the non-coding genome will unravel novel pathogenic mechanisms, opening new translational opportunities. Here, we present evidence of the possible involvement of many lncRNAs in the etiology of different forms of ID and NDD, grouping the candidate disease-genes in the most frequently affected cellular processes in which ID-risk genes were previously collected. We also illustrate new approaches for the identification and prioritization of NDD-risk lncRNAs, together with the current strategies to exploit them in diagnosis.
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