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1
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Kesler BK, Adams J, Neuert G. Transcriptional stochasticity reveals multiple mechanisms of long non-coding RNA regulation at the Xist-Tsix locus. Nat Commun 2025; 16:4223. [PMID: 40328749 PMCID: PMC12056010 DOI: 10.1038/s41467-025-59496-6] [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: 10/06/2023] [Accepted: 04/24/2025] [Indexed: 05/08/2025] Open
Abstract
Long noncoding RNAs (LncRNAs) are increasingly recognized as being involved in human physiology and diseases, but there is a lack of mechanistic understanding for the majority of lncRNAs. We comparatively test proposed mechanisms of antisense lncRNA regulation at the X-chromosome Inactivation (XCI) locus. We find that due to stochasticity in transcription, different mechanisms based on the act of transcription regulate Xist and Tsix at different levels of nascent transcription. At medium levels, RNA polymerases transcribe Xist and Tsix on each strand at the same transcription site and deposit significant amounts of the histone mark H3K36me3, which inhibits Xist. At high levels of nascent transcription, many RNA polymerases transcribe Xist or Tsix resulting in transcriptional interference. Therefore, lncRNA expression variability is not just a quirk of transcription but an important aspect of regulation that allows multiple mechanisms to be employed by the same gene locus within the same cell population.
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Affiliation(s)
- Benjamin K Kesler
- Department of Molecular Physiology and Biophysics, Basic Sciences, School of Medicine, Vanderbilt University, Nashville, TN, USA
| | - John Adams
- Department of Molecular Physiology and Biophysics, Basic Sciences, School of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Gregor Neuert
- Department of Molecular Physiology and Biophysics, Basic Sciences, School of Medicine, Vanderbilt University, Nashville, TN, USA.
- Department of Pharmacology, Basic Sciences, School of Medicine, Vanderbilt University, Nashville, TN, USA.
- Department of Biomedical Engineering, School of Engineering, Vanderbilt University, Nashville, TN, USA.
- Vanderbilt Center for Computational Systems Biology, Vanderbilt University, Nashville, TN, USA.
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2
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Aguilar R, Rosenberg M, Levy V, Lee JT. An evolving landscape of PRC2-RNA interactions in chromatin regulation. Nat Rev Mol Cell Biol 2025:10.1038/s41580-025-00850-3. [PMID: 40307460 DOI: 10.1038/s41580-025-00850-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2025] [Indexed: 05/02/2025]
Abstract
A major unsolved problem in epigenetics is how RNA regulates Polycomb repressive complex 2 (PRC2), a complex that trimethylates histone H3 Lys27 (H3K27me3) to form repressive chromatin. Key questions include how PRC2 binds RNA in vivo and what the functional consequences of binding are. In this Perspective, we expound on the viewpoint that RNA is integral to the stepwise regulation of PRC2 activity. Using the long non-coding RNA XIST and X chromosome inactivation as a model, we discuss evidence indicating that RNA is involved in PRC2 recruitment onto chromatin, in induction of its catalytic activity and in its eviction from chromatin. Studies have also implicated RNA in controlling promoter-proximal pausing of RNA polymerase II. The cumulative data argue that the functional consequences of PRC2-RNA interactions crucially depend on RNA conformation. We recognize that alternative hypotheses exist and therefore we attempt to integrate contrary data. Thus, although an RNA-rich landscape is emerging for Polycomb complexes, additional work is required to resolve a broad range of data interpretations.
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Affiliation(s)
- Rodrigo Aguilar
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Institute of Biomedical Sciences (ICB), Faculty of Medicine & Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
| | - Michael Rosenberg
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Institute of Nanotechnology and Advanced Materials, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
| | - Vered Levy
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
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3
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Ding M, Wang D, Chen H, Kesner B, Grimm NB, Weissbein U, Lappala A, Jiang J, Rivera C, Lou J, Li P, Lee JT. A biophysical basis for the spreading behavior and limited diffusion of Xist. Cell 2025; 188:978-997.e25. [PMID: 39824183 PMCID: PMC11863002 DOI: 10.1016/j.cell.2024.12.004] [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: 07/22/2024] [Revised: 11/04/2024] [Accepted: 12/06/2024] [Indexed: 01/20/2025]
Abstract
Xist RNA initiates X inactivation as it spreads in cis across the chromosome. Here, we reveal a biophysical basis for its cis-limited diffusion. Xist RNA and HNRNPK together drive a liquid-liquid phase separation (LLPS) that encapsulates the chromosome. HNRNPK droplets pull on Xist and internalize the RNA. Once internalized, Xist induces a further phase transition and "softens" the HNRNPK droplet. Xist alters the condensate's deformability, adhesiveness, and wetting properties in vitro. Other Xist-interacting proteins are internalized and entrapped within the droplet, resulting in a concentration of Xist and protein partners within the condensate. We attribute LLPS to HNRNPK's RGG and Xist's repeat B (RepB) motifs. Mutating these motifs causes Xist diffusion, disrupts polycomb recruitment, and precludes the required mixing of chromosomal compartments for Xist's migration. Thus, we hypothesize that phase transitions in HNRNPK condensates allow Xist to locally concentrate silencing factors and to spread through internal channels of the HNRNPK-encapsulated chromosome.
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Affiliation(s)
- Mingrui Ding
- State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Danni Wang
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Hui Chen
- Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Barry Kesner
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Niklas-Benedikt Grimm
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Universitat Pompeu Fabra (UPF), Barcelona, Spain; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Uri Weissbein
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Anna Lappala
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Jiying Jiang
- State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Carlos Rivera
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Jizhong Lou
- Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
| | - Pilong Li
- State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
| | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
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4
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Kriz AJ. HOMER for Analysis of Hi-C Data and Assessment of Composite Structure of the X Chromosome. Methods Mol Biol 2025; 2856:71-78. [PMID: 39283447 DOI: 10.1007/978-1-0716-4136-1_5] [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] [Indexed: 03/27/2025]
Abstract
Hi-C reads, which represent ligation events between different regions of the genome, must be processed into matrices of interaction frequencies for downstream analysis. Here, I describe a procedure for mapping Hi-C reads to the genome and conversion of mapped reads into the HOMER tag directory format and interaction matrix format for visualization with Juicebox. The method is demonstrated for the mouse composite X chromosome in which reads from the active and inactive X chromosomes are combined after mock DMSO treatment or targeted degradation of cohesin.
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Affiliation(s)
- Andrea J Kriz
- Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
- Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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5
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Wei C, Kesner B, Weissbein U, Wasserzug-Pash P, Das P, Lee JT. Dosage compensation of transposable elements in mammals. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.16.628797. [PMID: 39763768 PMCID: PMC11702583 DOI: 10.1101/2024.12.16.628797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
In mammals, X-linked dosage compensation involves two processes: X-chromosome inactivation (XCI) to balance X chromosome dosage between males and females, and hyperactivation of the remaining X chromosome (Xa-hyperactivation) to achieve X-autosome balance in both sexes. Studies of both processes have largely focused on coding genes and have not accounted for transposable elements (TEs) which comprise 50% of the X-chromosome, despite TEs being suspected to have numerous epigenetic functions. This oversight is due in part to the technical challenge of capturing repeat RNAs, bioinformatically aligning them, and determining allelic origin. To overcome these challenges, here we develop a new bioinformatic pipeline tailored to repetitive elements with capability for allelic discrimination. We then apply the pipeline to our recent So-Smart-Seq analysis of single embryos to comprehensively interrogate whether X-linked TEs are subject to either XCI or Xa-hyperactivation. With regards to XCI, we observe significant differences in TE silencing in parentally driven "imprinted" XCI versus zygotically driven "random" XCI. Chromosomal positioning and genetic background impact TE silencing. We also find that SINEs may influence 3D organization during XCI. In contrast, TEs do not undergo Xa-hyperactivation. Thus, while coding genes are subject to both forms of dosage compensation, TEs participate only in Xi silencing. Evolutionary and functional implications are discussed.
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Affiliation(s)
- Chunyao Wei
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Barry Kesner
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Uri Weissbein
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Peera Wasserzug-Pash
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Priyojit Das
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Jeannie T. Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
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6
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Zhao Z, Yang Y, Iqbal A, Wu Q, Zhou L. Biological Insights and Recent Advances in Plant Long Non-Coding RNA. Int J Mol Sci 2024; 25:11964. [PMID: 39596034 PMCID: PMC11593582 DOI: 10.3390/ijms252211964] [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: 10/22/2024] [Revised: 11/03/2024] [Accepted: 11/04/2024] [Indexed: 11/28/2024] Open
Abstract
Long non-coding RNA (lncRNA) refers to an RNA molecule longer than 200 nucleotides (nt) that plays a significant role in regulating essential molecular and biological processes. It is commonly found in animals, plants, and viruses, and is characterized by features such as epigenetic markers, developmental stage-specific expression, and tissue-specific expression. Research has shown that lncRNA participates in anatomical processes like plant progression, while also playing a crucial role in plant disease resistance and adaptation mechanisms. In this review, we provide a concise overview of the formation mechanism, structural characteristics, and databases related to lncRNA in recent years. We primarily discuss the biological roles of lncRNA in plant progression as well as its involvement in response to biotic and abiotic stresses. Additionally, we examine the current challenges associated with lncRNA and explore its potential application in crop production and breeding. Studying plant lncRNAs is highly significant for multiple reasons: It reveals the regulatory mechanisms of plant growth and development, promotes agricultural production and food security, and drives research in plant genomics and epigenetics. Additionally, it facilitates ecological protection and biodiversity conservation.
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Affiliation(s)
- Zhihao Zhao
- National Key Laboratory for Tropical Crop Breeding, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; (Z.Z.); (Y.Y.); (Q.W.)
- Hainan Key Laboratory of Tropical Oil Crops Biology/Coconut Research Institute, Chinese Academy of Tropical Agricultural Sciences, Wenchang 571339, China;
- Industrial Development Department, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China
| | - Yaodong Yang
- National Key Laboratory for Tropical Crop Breeding, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; (Z.Z.); (Y.Y.); (Q.W.)
- Hainan Key Laboratory of Tropical Oil Crops Biology/Coconut Research Institute, Chinese Academy of Tropical Agricultural Sciences, Wenchang 571339, China;
| | - Amjad Iqbal
- Hainan Key Laboratory of Tropical Oil Crops Biology/Coconut Research Institute, Chinese Academy of Tropical Agricultural Sciences, Wenchang 571339, China;
- Department of Food Science & Technology, Abdul Wali Khan University Mardan, Khyber Pakhtunkhwa 23200, Pakistan
| | - Qiufei Wu
- National Key Laboratory for Tropical Crop Breeding, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; (Z.Z.); (Y.Y.); (Q.W.)
- Hainan Key Laboratory of Tropical Oil Crops Biology/Coconut Research Institute, Chinese Academy of Tropical Agricultural Sciences, Wenchang 571339, China;
| | - Lixia Zhou
- National Key Laboratory for Tropical Crop Breeding, Chinese Academy of Tropical Agricultural Sciences, Haikou 571101, China; (Z.Z.); (Y.Y.); (Q.W.)
- Hainan Key Laboratory of Tropical Oil Crops Biology/Coconut Research Institute, Chinese Academy of Tropical Agricultural Sciences, Wenchang 571339, China;
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7
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Yao S, Jeon Y, Kesner B, Lee JT. Xist RNA binds select autosomal genes and depends on Repeat B to regulate their expression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.23.604772. [PMID: 39091753 PMCID: PMC11291044 DOI: 10.1101/2024.07.23.604772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Xist, a pivotal player in X chromosome inactivation (XCI), has long been perceived as a cis-acting long noncoding RNA that binds exclusively to the inactive X chromosome (Xi). However, Xist's ability to diffuse under select circumstances has also been documented, leading us to suspect that Xist RNA may have targets and functions beyond the Xi. Here, using female mouse embryonic stem cells (ES) and mouse embryonic fibroblasts (MEF) as models, we demonstrate that Xist RNA indeed can localize beyond the Xi. However, its binding is limited to ~100 genes in cells undergoing XCI (ES cells) and in post-XCI cells (MEFs). The target genes are diverse in function but are unified by their active chromatin status. Xist binds discretely to promoters of target genes in neighborhoods relatively depleted for Polycomb marks, contrasting with the broad, Polycomb-enriched domains reported for human XIST RNA. We find that Xist binding is associated with down-modulation of autosomal gene expression. However, unlike on the Xi, Xist binding does not lead to full silencing and also does not spread beyond the target gene. Over-expressing Xist in transgenic ES cells similarly leads to autosomal gene suppression, while deleting Xist's Repeat B motif reduces autosomal binding and perturbs autosomal down-regulation. Furthermore, treating female ES cells with the Xist inhibitor, X1, leads to loss of autosomal suppression. Altogether, our findings reveal that Xist targets ~100 genes beyond the Xi, identify Repeat B as a crucial domain for its in-trans function in mice, and indicate that autosomal targeting can be disrupted by a small molecule inhibitor.
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Affiliation(s)
- Shengze Yao
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Yesu Jeon
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Barry Kesner
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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8
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Barrero M, Lazarenkov A, Blanco E, Palma LG, López-Rubio AV, Bauer M, Bigas A, Di Croce L, Sardina JL, Payer B. The interferon γ pathway enhances pluripotency and X-chromosome reactivation in iPSC reprogramming. SCIENCE ADVANCES 2024; 10:eadj8862. [PMID: 39110794 PMCID: PMC11305397 DOI: 10.1126/sciadv.adj8862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 06/28/2024] [Indexed: 08/10/2024]
Abstract
Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) requires activation of the pluripotency network and resetting of the epigenome by erasing the epigenetic memory of the somatic state. In female mouse cells, a critical epigenetic reprogramming step is the reactivation of the inactive X chromosome. Despite its importance, a systematic understanding of the regulatory networks linking pluripotency and X-reactivation is missing. Here, we reveal important pathways for pluripotency acquisition and X-reactivation using a genome-wide CRISPR screen during neural precursor to iPSC reprogramming. In particular, we discover that activation of the interferon γ (IFNγ) pathway early during reprogramming accelerates pluripotency acquisition and X-reactivation. IFNγ stimulates STAT3 signaling and the pluripotency network and leads to enhanced TET-mediated DNA demethylation, which consequently boosts X-reactivation. We therefore gain a mechanistic understanding of the role of IFNγ in reprogramming and X-reactivation and provide a comprehensive resource of the molecular networks involved in these processes.
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Affiliation(s)
- Mercedes Barrero
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain
| | | | - Enrique Blanco
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain
| | - Luis G. Palma
- Josep Carreras Leukemia Research Institute (IJC), Badalona 08916, Spain
- Institut Hospital del Mar d’Investigacions Mèdiques, CIBERONC, Barcelona 08003, Spain
| | | | - Moritz Bauer
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain
| | - Anna Bigas
- Josep Carreras Leukemia Research Institute (IJC), Badalona 08916, Spain
- Institut Hospital del Mar d’Investigacions Mèdiques, CIBERONC, Barcelona 08003, Spain
| | - Luciano Di Croce
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain
- Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
- ICREA, Passeig Lluís Companys 23, Barcelona 08010, Spain
| | - José Luis Sardina
- Josep Carreras Leukemia Research Institute (IJC), Badalona 08916, Spain
| | - Bernhard Payer
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain
- Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
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9
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Heydari R, Karimi P, Meyfour A. Long non-coding RNAs as pathophysiological regulators, therapeutic targets and novel extracellular vesicle biomarkers for the diagnosis of inflammatory bowel disease. Biomed Pharmacother 2024; 176:116868. [PMID: 38850647 DOI: 10.1016/j.biopha.2024.116868] [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: 04/07/2024] [Revised: 05/27/2024] [Accepted: 06/03/2024] [Indexed: 06/10/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing disease of the gastrointestinal (GI) system that includes two groups, Crohn's disease (CD) and ulcerative colitis (UC). To cope with these two classes of IBD, the investigation of pathogenic mechanisms and the discovery of new diagnostic and therapeutic approaches are crucial. Long non-coding RNAs (lncRNAs) which are non-coding RNAs with a length of longer than 200 nucleotides have indicated significant association with the pathology of IBD and strong potential to be used as accurate biomarkers in diagnosing and predicting responses to the IBD treatment. In the current review, we aim to investigate the role of lncRNAs in the pathology and development of IBD. We first describe recent advances in research on dysregulated lncRNAs in the pathogenesis of IBD from the perspective of epithelial barrier function, intestinal immunity, mitochondrial function, and intestinal autophagy. Then, we highlight the possible translational role of lncRNAs as therapeutic targets, diagnostic biomarkers, and predictors of therapeutic response in colon tissues and plasma samples. Finally, we discuss the potential of extracellular vesicles and their lncRNA cargo in the pathophysiology, diagnosis, and treatment of IBD.
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Affiliation(s)
- Raheleh Heydari
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Padideh Karimi
- CRTD/Center for Regenerative Therapies Dresden, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Dresden 01307, Germany
| | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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10
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Lee YW, Weissbein U, Blum R, Lee JT. G-quadruplex folding in Xist RNA antagonizes PRC2 activity for stepwise regulation of X chromosome inactivation. Mol Cell 2024; 84:1870-1885.e9. [PMID: 38759625 PMCID: PMC11505738 DOI: 10.1016/j.molcel.2024.04.015] [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: 05/31/2023] [Revised: 11/25/2023] [Accepted: 04/19/2024] [Indexed: 05/19/2024]
Abstract
How Polycomb repressive complex 2 (PRC2) is regulated by RNA remains an unsolved problem. Although PRC2 binds G-tracts with the potential to form RNA G-quadruplexes (rG4s), whether rG4s fold extensively in vivo and whether PRC2 binds folded or unfolded rG4 are unknown. Using the X-inactivation model in mouse embryonic stem cells, here we identify multiple folded rG4s in Xist RNA and demonstrate that PRC2 preferentially binds folded rG4s. High-affinity rG4 binding inhibits PRC2's histone methyltransferase activity, and stabilizing rG4 in vivo antagonizes H3 at lysine 27 (H3K27me3) enrichment on the inactive X chromosome. Surprisingly, mutagenizing the rG4 does not affect PRC2 recruitment but promotes its release and catalytic activation on chromatin. H3K27me3 marks are misplaced, however, and gene silencing is compromised. Xist-PRC2 complexes become entrapped in the S1 chromosome compartment, precluding the required translocation into the S2 compartment. Thus, Xist rG4 folding controls PRC2 activity, H3K27me3 enrichment, and the stepwise regulation of chromosome-wide gene silencing.
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Affiliation(s)
- Yong Woo Lee
- Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - Uri Weissbein
- Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - Roy Blum
- Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
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11
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Lu J, Xu L, Wang Y, Guan B. lncRNAs regulate cell stemness in physiology and pathology during differentiation and development. AMERICAN JOURNAL OF STEM CELLS 2024; 13:59-74. [PMID: 38765805 PMCID: PMC11101988 DOI: 10.62347/vhvu7361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 03/06/2024] [Indexed: 05/22/2024]
Abstract
Long non-coding RNA (lncRNA) are an important class of ubiquitous genes involved in diverse biological functions. lncRNAs, defined as noncoding RNAs with a length exceeding 200 nucleotides, are abundantly expressed throughout cells; however, their precise functions remain largely elusive. From embryonic stem cell proliferation and differentiation to cancer cell proliferation and invasion, lncRNAs play multifaceted regulatory roles across various cellular stages. Moreover, lncRNAs participate in the regulation of differentiation and regeneration during cellular development processes while also playing a pivotal role in maintaining and regulating cell stemness. In this article, we comprehensively review the current knowledge regarding lncRNAs in this field, discussing their biological functions and mechanisms underlying stemness regulation along with the factors implicated in these processes. We emphasize the growing evidence supporting the significance of lncRNAs in governing cell stemness while indicating that disruptions or mutations within them may serve as fundamental causes for certain developmental disorders.
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Affiliation(s)
- Jie Lu
- Department of Otolaryngology Head and Neck Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University Yangzhou, Jiangsu, China
| | - Li Xu
- Department of Otolaryngology Head and Neck Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University Yangzhou, Jiangsu, China
| | - Ying Wang
- Department of Otolaryngology Head and Neck Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University Yangzhou, Jiangsu, China
| | - Bing Guan
- Department of Otolaryngology Head and Neck Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University Yangzhou, Jiangsu, China
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12
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Wei C, Kesner B, Yin H, Lee JT. Imprinted X chromosome inactivation at the gamete-to-embryo transition. Mol Cell 2024; 84:1442-1459.e7. [PMID: 38458200 PMCID: PMC11031340 DOI: 10.1016/j.molcel.2024.02.013] [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: 07/22/2023] [Revised: 12/23/2023] [Accepted: 02/13/2024] [Indexed: 03/10/2024]
Abstract
In mammals, dosage compensation involves two parallel processes: (1) X inactivation, which equalizes X chromosome dosage between males and females, and (2) X hyperactivation, which upregulates the active X for X-autosome balance. The field currently favors models whereby dosage compensation initiates "de novo" during mouse development. Here, we develop "So-Smart-seq" to revisit the question and interrogate a comprehensive transcriptome including noncoding genes and repeats in mice. Intriguingly, de novo silencing pertains only to a subset of Xp genes. Evolutionarily older genes and repetitive elements demonstrate constitutive Xp silencing, adopt distinct signatures, and do not require Xist to initiate silencing. We trace Xp silencing backward in developmental time to meiotic sex chromosome inactivation in the male germ line and observe that Xm hyperactivation is timed to Xp silencing on a gene-by-gene basis. Thus, during the gamete-to-embryo transition, older Xp genes are transmitted in a "pre-inactivated" state. These findings have implications for the evolution of imprinting.
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Affiliation(s)
- Chunyao Wei
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Barry Kesner
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Hao Yin
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
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13
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Wang Q, Deng J, Jiang Y, Wang Z, Xia B, Chen T. A medaka gonad-specific lncRNA may act as pri-miR-202 to regulate testicular endocrine homeostasis and spermatogenesis. Theriogenology 2024; 214:273-285. [PMID: 37948817 DOI: 10.1016/j.theriogenology.2023.10.020] [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: 05/09/2023] [Revised: 10/09/2023] [Accepted: 10/15/2023] [Indexed: 11/12/2023]
Abstract
A large number of long non-coding RNAs (lncRNAs) are expressed in animal gonads, but their functions are poorly understood. In this study, a gonad-specific lncRNA, termed lnc4, was identified and characterized in the model fish medaka (Oryzias latipes). The expression pattern and in vitro functional analyses indicated that lnc4 was likely to be a primary transcript of miR-202 (pri-miR-202). Results of single-molecule fluorescence in situ hybridization demonstrated that the precursor miR-202 (pre-miR-202) was highly expressed in the nuclei of testicular somatic cells, including Leydig and Sertoli cells, whereas only a small amount of lnc4 molecules could be detected co-expressed with pre-miR-202 in Sertoli cells due to its low expression level. Deletion of the lnc4 locus led to a significant reduction in testis size and a dramatic decrease in the number of male germ cells, as well as a reduction in sperm viability. Moreover, lnc4 knockout resulted in enhanced synthesis and secretion of testicular somatic cells and accelerated differentiation of immature male germ cells. Taken together, functional studies of lnc4 and its mature transcript miR-202 will contribute to the understanding of the important role of non-coding RNAs in animal or human reproductive disorders.
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Affiliation(s)
- Qian Wang
- College of Animal Science and Technology, Yangtze University, Jingzhou, Hubei, 434024, China; College of Fisheries, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Jiajie Deng
- State Key Laboratory of Freshwater Ecology and Biotechnology, Hubei Hongshan Laboratory, Institute of Hydrobiology, Innovation Academy for Seed Design (INASEED), Chinese Academy of Sciences, Wuhan, Hubei, 430072, China
| | - Yuewen Jiang
- College of Fisheries, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Zhi Wang
- College of Fisheries, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Bilin Xia
- College of Fisheries, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Tiansheng Chen
- Fisheries College of Jimei University, Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture and Rural Affairs, Engineering Research Center of the Modern Technology for Eel Industry, Ministry of Education, Xiamen, Fujian, 361021, China; College of Fisheries, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
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14
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Chen J, Huang CP, Quan C, Zu X, Ou Z, Tsai YC, Messing E, Yeh S, Chang C. The androgen receptor in bladder cancer. Nat Rev Urol 2023; 20:560-574. [PMID: 37072491 DOI: 10.1038/s41585-023-00761-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2023] [Indexed: 04/20/2023]
Abstract
Bladder cancer is the ninth most common cancer worldwide with a striking sex-based difference in incidence. Emerging evidence indicates that the androgen receptor (AR) might promote the development, progression and recurrence of bladder cancer, contributing to the observed sex differences. Targeting androgen-AR signalling has promise as potential therapy for bladder cancer and helps to suppress progression of this disease. In addition, the identification of a new membrane AR and AR-regulated non-coding RNAs has important implications for bladder cancer treatment. The success of human clinical trials of targeted-AR therapies will help in the development of improved treatments for patients with bladder cancer.
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Affiliation(s)
- Jinbo Chen
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Chi-Ping Huang
- Department of Urology, China Medical University Hospital, Taichung, Taiwan
| | - Chao Quan
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiongbing Zu
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
| | - Zhenyu Ou
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Yu-Chieh Tsai
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Edward Messing
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Shuyuan Yeh
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Chawnshang Chang
- Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
- Department of Urology, China Medical University Hospital, Taichung, Taiwan.
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15
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Mosca N, Russo A, Potenza N. Making Sense of Antisense lncRNAs in Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:8886. [PMID: 37240232 PMCID: PMC10219390 DOI: 10.3390/ijms24108886] [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: 04/25/2023] [Revised: 05/14/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Transcriptome complexity is emerging as an unprecedented and fascinating domain, especially by high-throughput sequencing technologies that have unveiled a plethora of new non-coding RNA biotypes. This review covers antisense long non-coding RNAs, i.e., lncRNAs transcribed from the opposite strand of other known genes, and their role in hepatocellular carcinoma (HCC). Several sense-antisense transcript pairs have been recently annotated, especially from mammalian genomes, and an understanding of their evolutionary sense and functional role for human health and diseases is only beginning. Antisense lncRNAs dysregulation is significantly involved in hepatocarcinogenesis, where they can act as oncogenes or oncosuppressors, thus playing a key role in tumor onset, progression, and chemoradiotherapy response, as deduced from many studies discussed here. Mechanistically, antisense lncRNAs regulate gene expression by exploiting various molecular mechanisms shared with other ncRNA molecules, and exploit special mechanisms on their corresponding sense gene due to sequence complementarity, thus exerting epigenetic, transcriptional, post-transcriptional, and translational controls. The next challenges will be piecing together the complex RNA regulatory networks driven by antisense lncRNAs and, ultimately, assigning them a function in physiological and pathological contexts, in addition to defining prospective novel therapeutic targets and innovative diagnostic tools.
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Affiliation(s)
| | | | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (N.M.); (A.R.)
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16
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Kravitz SN, Ferris E, Love MI, Thomas A, Quinlan AR, Gregg C. Random allelic expression in the adult human body. Cell Rep 2023; 42:111945. [PMID: 36640362 PMCID: PMC10484211 DOI: 10.1016/j.celrep.2022.111945] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 10/17/2022] [Accepted: 12/15/2022] [Indexed: 01/07/2023] Open
Abstract
Genes are typically assumed to express both parental alleles similarly, yet cell lines show random allelic expression (RAE) for many autosomal genes that could shape genetic effects. Thus, understanding RAE in human tissues could improve our understanding of phenotypic variation. Here, we develop a methodology to perform genome-wide profiling of RAE and biallelic expression in GTEx datasets for 832 people and 54 tissues. We report 2,762 autosomal genes with some RAE properties similar to randomly inactivated X-linked genes. We found that RAE is associated with rapidly evolving regions in the human genome, adaptive signaling processes, and genes linked to age-related diseases such as neurodegeneration and cancer. We define putative mechanistic subtypes of RAE distinguished by gene overlaps on sense and antisense DNA strands, aggregation in clusters near telomeres, and increased regulatory complexity and inputs compared with biallelic genes. We provide foundations to study RAE in human phenotypes, evolution, and disease.
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Affiliation(s)
- Stephanie N Kravitz
- Department of Human Genetics, University of Utah, Salt Lake City, UT, USA; Neurobiology, University of Utah, Salt Lake City, UT, USA
| | - Elliott Ferris
- Neurobiology, University of Utah, Salt Lake City, UT, USA
| | - Michael I Love
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Alun Thomas
- Department of Internal Medicine, Epidemiology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Aaron R Quinlan
- Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
| | - Christopher Gregg
- Department of Human Genetics, University of Utah, Salt Lake City, UT, USA; Neurobiology, University of Utah, Salt Lake City, UT, USA.
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17
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Xuan C, Yang E, Zhao S, Xu J, Li P, Zhang Y, Jiang Z, Ding X. Regulation of LncRNAs and microRNAs in neuronal development and disease. PeerJ 2023; 11:e15197. [PMID: 37038472 PMCID: PMC10082570 DOI: 10.7717/peerj.15197] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 03/15/2023] [Indexed: 04/12/2023] Open
Abstract
Non-coding RNAs (ncRNAs) are RNAs that do not encode proteins but play important roles in regulating cellular processes. Multiple studies over the past decade have demonstrated the role of microRNAs (miRNAs) in cancer, in which some miRNAs can act as biomarkers or provide therapy target. Accumulating evidence also points to the importance of long non-coding RNAs (lncRNAs) in regulating miRNA-mRNA networks. An increasing number of ncRNAs have been shown to be involved in the regulation of cellular processes, and dysregulation of ncRNAs often heralds disease. As the population ages, the incidence of neurodegenerative diseases is increasing, placing enormous pressure on global health systems. Given the excellent performance of ncRNAs in early cancer screening and treatment, here we attempted to aggregate and analyze the regulatory functions of ncRNAs in neuronal development and disease. In this review, we summarize current knowledge on ncRNA taxonomy, biogenesis, and function, and discuss current research progress on ncRNAs in relation to neuronal development, differentiation, and neurodegenerative diseases.
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Affiliation(s)
- Cheng Xuan
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Enyu Yang
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Shuo Zhao
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Juan Xu
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Peihang Li
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
| | - Yaping Zhang
- Department of Oncology, Zhejiang Xiaoshan Hospital, Hangzhou, Zhejiang Province, China
| | - Zhenggang Jiang
- Department of Science Research and Information Management, Zhejiang Provincial Centers for Disease Control and Prevention, Hangzhou, Zhejiang Province, China
| | - Xianfeng Ding
- College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China
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18
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Huang X, Shi Y, Yan J, Qu W, Li X, Tan J. LPI-CSFFR: Combining serial fusion with feature reuse for predicting LncRNA-protein interactions. Comput Biol Chem 2022; 99:107718. [PMID: 35785626 DOI: 10.1016/j.compbiolchem.2022.107718] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/24/2022] [Accepted: 06/22/2022] [Indexed: 11/03/2022]
Abstract
Long non-coding RNAs (LncRNAs) play important roles in a series of life activities, and they function primarily with proteins. The wet experimental-based methods in lncRNA-protein interactions (lncRPIs) study are time-consuming and expensive. In this study, we propose for the first time a novel feature fusion method, the LPI-CSFFR, to train and predict LncRPIs based on a Convolutional Neural Network (CNN) with feature reuse and serial fusion in sequences, secondary structures, and physicochemical properties of proteins and lncRNAs. The experimental results indicate that LPI-CSFFR achieves excellent performance on the datasets RPI1460 and RPI1807 with an accuracy of 83.7 % and 98.1 %, respectively. We further compare LPI-CSFFR with the state-of-the-art existing methods on the same benchmark datasets to evaluate the performance. In addition, to test the generalization performance of the model, we independently test sample pairs of five model organisms, where Mus musculus are the highest prediction accuracy of 99.5 %, and we find multiple hotspot proteins after constructing an interaction network. Finally, we test the predictive power of the LPI-CSFFR for sample pairs with unknown interactions. The results indicate that LPI-CSFFR is promising for predicting potential LncRPIs. The relevant source code and the data used in this study are available at https://github.com/JianjunTan-Beijing/LPI-CSFFR.
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Affiliation(s)
- Xiaoqian Huang
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing International Science and Technology Cooperation Base for Intelligent Physiological Measurement and Clinical Transformation, Beijing 100124, China
| | - Yi Shi
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing International Science and Technology Cooperation Base for Intelligent Physiological Measurement and Clinical Transformation, Beijing 100124, China
| | - Jing Yan
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing International Science and Technology Cooperation Base for Intelligent Physiological Measurement and Clinical Transformation, Beijing 100124, China
| | - Wenyan Qu
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing International Science and Technology Cooperation Base for Intelligent Physiological Measurement and Clinical Transformation, Beijing 100124, China
| | - Xiaoyi Li
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing International Science and Technology Cooperation Base for Intelligent Physiological Measurement and Clinical Transformation, Beijing 100124, China
| | - Jianjun Tan
- Department of Biomedical Engineering, Faculty of Environment and Life, Beijing University of Technology, Beijing International Science and Technology Cooperation Base for Intelligent Physiological Measurement and Clinical Transformation, Beijing 100124, China.
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19
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Severino J, Bauer M, Mattimoe T, Arecco N, Cozzuto L, Lorden P, Hamada N, Nosaka Y, Nagaoka SI, Audergon P, Tarruell A, Heyn H, Hayashi K, Saitou M, Payer B. Controlled X-chromosome dynamics defines meiotic potential of female mouse in vitro germ cells. EMBO J 2022; 41:e109457. [PMID: 35603814 PMCID: PMC9194795 DOI: 10.15252/embj.2021109457] [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: 08/16/2021] [Revised: 04/08/2022] [Accepted: 04/14/2022] [Indexed: 11/23/2022] Open
Abstract
The mammalian germline is characterized by extensive epigenetic reprogramming during its development into functional eggs and sperm. Specifically, the epigenome requires resetting before parental marks can be established and transmitted to the next generation. In the female germline, X‐chromosome inactivation and reactivation are among the most prominent epigenetic reprogramming events, yet very little is known about their kinetics and biological function. Here, we investigate X‐inactivation and reactivation dynamics using a tailor‐made in vitro system of primordial germ cell‐like cell (PGCLC) differentiation from mouse embryonic stem cells. We find that X‐inactivation in PGCLCs in vitro and in germ cell‐competent epiblast cells in vivo is moderate compared to somatic cells, and frequently characterized by escaping genes. X‐inactivation is followed by step‐wise X‐reactivation, which is mostly completed during meiotic prophase I. Furthermore, we find that PGCLCs which fail to undergo X‐inactivation or reactivate too rapidly display impaired meiotic potential. Thus, our data reveal fine‐tuned X‐chromosome remodelling as a critical feature of female germ cell development towards meiosis and oogenesis.
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Affiliation(s)
- Jacqueline Severino
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Moritz Bauer
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Tom Mattimoe
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Niccolò Arecco
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Luca Cozzuto
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Patricia Lorden
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Norio Hamada
- Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshiaki Nosaka
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan.,Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - So I Nagaoka
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan.,Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Pauline Audergon
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Antonio Tarruell
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Holger Heyn
- CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Katsuhiko Hayashi
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mitinori Saitou
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan.,Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Bernhard Payer
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,Universitat Pompeu Fabra (UPF), Barcelona, Spain
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20
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Aguilar R, Spencer KB, Kesner B, Rizvi NF, Badmalia MD, Mrozowich T, Mortison JD, Rivera C, Smith GF, Burchard J, Dandliker PJ, Patel TR, Nickbarg EB, Lee JT. Targeting Xist with compounds that disrupt RNA structure and X inactivation. Nature 2022; 604:160-166. [PMID: 35355011 PMCID: PMC11549687 DOI: 10.1038/s41586-022-04537-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 02/08/2022] [Indexed: 12/13/2022]
Abstract
Although more than 98% of the human genome is non-coding1, nearly all of the drugs on the market target one of about 700 disease-related proteins. The historical reluctance to invest in non-coding RNA stems partly from requirements for drug targets to adopt a single stable conformation2. Most RNAs can adopt several conformations of similar stabilities. RNA structures also remain challenging to determine3. Nonetheless, an increasing number of diseases are now being attributed to non-coding RNA4 and the ability to target them would vastly expand the chemical space for drug development. Here we devise a screening strategy and identify small molecules that bind the non-coding RNA prototype Xist5. The X1 compound has drug-like properties and binds specifically the RepA motif6 of Xist in vitro and in vivo. Small-angle X-ray scattering analysis reveals that RepA can adopt multiple conformations but favours one structure in solution. X1 binding reduces the conformational space of RepA, displaces cognate interacting protein factors (PRC2 and SPEN), suppresses histone H3K27 trimethylation, and blocks initiation of X-chromosome inactivation. X1 inhibits cell differentiation and growth in a female-specific manner. Thus, RNA can be systematically targeted by drug-like compounds that disrupt RNA structure and epigenetic function.
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Affiliation(s)
- Rodrigo Aguilar
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Institute of Biomedical Sciences (ICB), Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
| | | | - Barry Kesner
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | | | - Maulik D Badmalia
- Alberta RNA Research and Training Institute, Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta, Canada
| | - Tyler Mrozowich
- Alberta RNA Research and Training Institute, Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta, Canada
| | | | - Carlos Rivera
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | | | | | | | - Trushar R Patel
- Alberta RNA Research and Training Institute, Department of Chemistry and Biochemistry, University of Lethbridge, Lethbridge, Alberta, Canada
| | | | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
- Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
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21
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Abstract
Recently an explosion in the discovery of long noncoding RNAs (lncRNAs) was obtained by high-throughput sequencing. Genome-wide transcriptome analyses, in conjugation with research for epigenetic modifications of chromatins, identified a novel type of non-protein coding transcripts longer than 200 nucleotides named lncRNAs . They are gradually emerging as functional and critical participants in many physiological processes. Here we gave an overview of the characteristics, biological functions, and working mechanism for this new class of noncoding RNA molecules.
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22
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Oh HJ, Aguilar R, Kesner B, Lee HG, Kriz AJ, Chu HP, Lee JT. Jpx RNA regulates CTCF anchor site selection and formation of chromosome loops. Cell 2021; 184:6157-6173.e24. [PMID: 34856126 DOI: 10.1016/j.cell.2021.11.012] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 09/22/2021] [Accepted: 11/09/2021] [Indexed: 01/24/2023]
Abstract
Chromosome loops shift dynamically during development, homeostasis, and disease. CCCTC-binding factor (CTCF) is known to anchor loops and construct 3D genomes, but how anchor sites are selected is not yet understood. Here, we unveil Jpx RNA as a determinant of anchor selectivity. Jpx RNA targets thousands of genomic sites, preferentially binding promoters of active genes. Depleting Jpx RNA causes ectopic CTCF binding, massive shifts in chromosome looping, and downregulation of >700 Jpx target genes. Without Jpx, thousands of lost loops are replaced by de novo loops anchored by ectopic CTCF sites. Although Jpx controls CTCF binding on a genome-wide basis, it acts selectively at the subset of developmentally sensitive CTCF sites. Specifically, Jpx targets low-affinity CTCF motifs and displaces CTCF protein through competitive inhibition. We conclude that Jpx acts as a CTCF release factor and shapes the 3D genome by regulating anchor site usage.
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Affiliation(s)
- Hyun Jung Oh
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - Rodrigo Aguilar
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - Barry Kesner
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - Hun-Goo Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - Andrea J Kriz
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - Hsueh-Ping Chu
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
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23
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Khazeei Tabari MA, Mishan MA, Moradi M, Khandan M, Khoshhal H, Mahrooz A, Bagheri A. Noncoding RNA Roles in Pharmacogenomic Responses to Aspirin: New Molecular Mechanisms for an Old Drug. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6830560. [PMID: 34926688 PMCID: PMC8677408 DOI: 10.1155/2021/6830560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 11/25/2021] [Indexed: 12/13/2022]
Abstract
Aspirin, as one of the most frequently prescribed drugs, can have therapeutic effects on different conditions such as cardiovascular and metabolic disorders and malignancies. The effects of this common cardiovascular drug are exerted through different molecular and cellular pathways. Altered noncoding RNA (ncRNA) expression profiles during aspirin treatments indicate a close relationship between these regulatory molecules and aspirin effects through regulating gene expressions. A better understanding of the molecular networks contributing to aspirin efficacy would help optimize efficient therapies for this very popular drug. This review is aimed at discussing and highlighting the identified interactions between aspirin and ncRNAs and their targeting pathways and better understanding pharmacogenetic responses to aspirin.
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Affiliation(s)
- Mohammad Amin Khazeei Tabari
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
- USERN Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohammad Amir Mishan
- Ocular Tissue Engineering Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mona Moradi
- Department of Clinical Biochemistry and Medical Genetics, Faculty of Medicine, Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohanna Khandan
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
- USERN Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hooman Khoshhal
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
- USERN Office, Mazandaran University of Medical Sciences, Sari, Iran
| | - Abdolkarim Mahrooz
- Department of Clinical Biochemistry and Medical Genetics, Faculty of Medicine, Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Abouzar Bagheri
- Department of Clinical Biochemistry and Medical Genetics, Faculty of Medicine, Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran
- Department of Clinical Biochemistry and Medical Genetics, Gastrointestinal Cancer Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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24
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Burton NO, Greer EL. Multigenerational epigenetic inheritance: Transmitting information across generations. Semin Cell Dev Biol 2021; 127:121-132. [PMID: 34426067 DOI: 10.1016/j.semcdb.2021.08.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 01/07/2023]
Abstract
Inherited epigenetic information has been observed to regulate a variety of complex organismal phenotypes across diverse taxa of life. This continually expanding body of literature suggests that epigenetic inheritance plays a significant, and potentially fundamental, role in inheritance. Despite the important role these types of effects play in biology, the molecular mediators of this non-genetic transmission of information are just now beginning to be deciphered. Here we provide an intellectual framework for interpreting these findings and how they can interact with each other. We also define the different types of mechanisms that have been found to mediate epigenetic inheritance and to regulate whether epigenetic information persists for one or many generations. The field of epigenetic inheritance is entering an exciting phase, in which we are beginning to understand the mechanisms by which non-genetic information is transmitted to, and deciphered by, subsequent generations to maintain essential environmental information without permanently altering the genetic code. A more complete understanding of how and when epigenetic inheritance occurs will advance our understanding of numerous different aspects of biology ranging from how organisms cope with changing environments to human pathologies influenced by a parent's environment.
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Affiliation(s)
- Nicholas O Burton
- Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK; Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Center for Epigenetics, Van Andel Institute, Grand Rapids, MI 49503, USA.
| | - Eric L Greer
- Division of Newborn Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Harvard Medical School Initiative for RNA Medicine, Boston, MA 02115, USA.
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25
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Szanto A, Aguilar R, Kesner B, Blum R, Wang D, Cifuentes-Rojas C, Del Rosario BC, Kis-Toth K, Lee JT. A disproportionate impact of G9a methyltransferase deficiency on the X chromosome. Genes Dev 2021; 35:1035-1054. [PMID: 34168040 PMCID: PMC8247598 DOI: 10.1101/gad.337592.120] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 05/27/2021] [Indexed: 01/05/2023]
Abstract
In this study from Szanto et al., the authors investigated the role of G9a, a histone methyltransferase responsible for the dimethylation of histone H3 at lysine 9 (H3K9me2) that plays key roles in transcriptional silencing of developmentally regulated genes, in X-chromosome inactivation (XCI). They found a female-specific function of G9a and demonstrate that deleting G9a has a disproportionate impact on the X chromosome relative to the rest of the genome, and show RNA tethers G9a for allele-specific targeting of the H3K9me2 modification and the G9a–RNA interaction is essential for XCI. G9a is a histone methyltransferase responsible for the dimethylation of histone H3 at lysine 9 (H3K9me2). G9a plays key roles in transcriptional silencing of developmentally regulated genes, but its role in X-chromosome inactivation (XCI) has been under debate. Here, we uncover a female-specific function of G9a and demonstrate that deleting G9a has a disproportionate impact on the X chromosome relative to the rest of the genome. G9a deficiency causes a failure of XCI and female-specific hypersensitivity to drug inhibition of H3K9me2. We show that G9a interacts with Tsix and Xist RNAs, and that competitive inhibition of the G9a-RNA interaction recapitulates the XCI defect. During XCI, Xist recruits G9a to silence X-linked genes on the future inactive X. In parallel on the future Xa, Tsix recruits G9a to silence Xist in cis. Thus, RNA tethers G9a for allele-specific targeting of the H3K9me2 modification and the G9a-RNA interaction is essential for XCI.
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Affiliation(s)
- Attila Szanto
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.,Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Rodrigo Aguilar
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.,Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Barry Kesner
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.,Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Roy Blum
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.,Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Danni Wang
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.,Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Catherine Cifuentes-Rojas
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.,Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Brian C Del Rosario
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.,Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Katalin Kis-Toth
- Department of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, Massachusetts 02115, USA
| | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.,Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
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26
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Yin H, Wei C, Lee JT. Revisiting the consequences of deleting the X inactivation center. Proc Natl Acad Sci U S A 2021; 118:e2102683118. [PMID: 34161282 PMCID: PMC8237661 DOI: 10.1073/pnas.2102683118] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Mammalian cells equalize X-linked dosages between the male (XY) and female (XX) sexes by silencing one X chromosome in the female sex. This process, known as "X chromosome inactivation" (XCI), requires a master switch within the X inactivation center (Xic). The Xic spans several hundred kilobases in the mouse and includes a number of regulatory noncoding genes that produce functional transcripts. Over three decades, transgenic and deletional analyses have demonstrated both the necessity and sufficiency of the Xic to induce XCI, including the steps of X chromosome counting, choice, and initiation of whole-chromosome silencing. One recent study, however, reported that deleting the noncoding sequences of the Xic surprisingly had no effect for XCI and attributed a sufficiency to drive counting to the coding gene, Rnf12/Rlim Here, we revisit the question by creating independent Xic deletion cell lines. Multiple independent clones carrying heterozygous deletions of the Xic display an inability to up-regulate Xist expression, consistent with a counting defect. This defect is rescued by a second site mutation in Tsix occurring in trans, bypassing the defect in counting. These findings reaffirm the essential nature of noncoding Xic elements for the initiation of XCI.
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Affiliation(s)
- Hao Yin
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114
- Department of Genetics, Harvard Medical School, Boston, MA 02114
| | - Chunyao Wei
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114
- Department of Genetics, Harvard Medical School, Boston, MA 02114
| | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114;
- Department of Genetics, Harvard Medical School, Boston, MA 02114
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27
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Chromosome compartments on the inactive X guide TAD formation independently of transcription during X-reactivation. Nat Commun 2021; 12:3499. [PMID: 34108480 PMCID: PMC8190187 DOI: 10.1038/s41467-021-23610-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 05/10/2021] [Indexed: 12/21/2022] Open
Abstract
A hallmark of chromosome organization is the partition into transcriptionally active A and repressed B compartments, and into topologically associating domains (TADs). Both structures were regarded to be absent from the inactive mouse X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, we combine a tailor-made mouse iPSC reprogramming system and high-resolution Hi-C to produce a time course combining gene reactivation, chromatin opening and chromosome topology during X-reactivation. Contrary to previous observations, we observe A/B-like compartments on the inactive X harbouring multiple subcompartments. While partial X-reactivation initiates within a compartment rich in X-inactivation escapees, it then occurs rapidly along the chromosome, concomitant with downregulation of Xist. Importantly, we find that TAD formation precedes transcription and initiates from Xist-poor compartments. Here, we show that TAD formation and transcriptional reactivation are causally independent during X-reactivation while establishing Xist as a common denominator.
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28
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Xu J, Zhao X, Mao F, Basrur V, Ueberheide B, Chait BT, Allis CD, Taverna SD, Gao S, Wang W, Liu Y. A Polycomb repressive complex is required for RNAi-mediated heterochromatin formation and dynamic distribution of nuclear bodies. Nucleic Acids Res 2021; 49:5407-5425. [PMID: 33412588 PMCID: PMC8191774 DOI: 10.1093/nar/gkaa1262] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 12/02/2020] [Accepted: 01/04/2021] [Indexed: 01/17/2023] Open
Abstract
Polycomb group (PcG) proteins are widely utilized for transcriptional repression in eukaryotes. Here, we characterize, in the protist Tetrahymena thermophila, the EZL1 (E(z)-like 1) complex, with components conserved in metazoan Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2). The EZL1 complex is required for histone H3 K27 and K9 methylation, heterochromatin formation, transposable element control, and programmed genome rearrangement. The EZL1 complex interacts with EMA1, a helicase required for RNA interference (RNAi). This interaction is implicated in co-transcriptional recruitment of the EZL1 complex. Binding of H3K27 and H3K9 methylation by PDD1-another PcG protein interacting with the EZL1 complex-reinforces its chromatin association. The EZL1 complex is an integral part of Polycomb bodies, which exhibit dynamic distribution in Tetrahymena development: Their dispersion is driven by chromatin association, while their coalescence by PDD1, likely via phase separation. Our results provide a molecular mechanism connecting RNAi and Polycomb repression, which coordinately regulate nuclear bodies and reorganize the genome.
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Affiliation(s)
- Jing Xu
- School of Life Science, Shanxi University, Taiyuan, Shanxi 030006, China
| | - Xiaolu Zhao
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China
| | - Fengbiao Mao
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Venkatesha Basrur
- Proteomics Resource Facility, Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Beatrix Ueberheide
- Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, the Rockefeller University, New York, NY 10065, USA
| | - Brian T Chait
- Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, the Rockefeller University, New York, NY 10065, USA
| | - C David Allis
- Laboratory of Chromatin Biology and Epigenetics, the Rockefeller University, New York, NY 10065, USA
| | - Sean D Taverna
- Department of Pharmacology and Molecular Sciences and the Center for Epigenetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Shan Gao
- Institute of Evolution & Marine Biodiversity, Ocean University of China, Qingdao 266003, China
| | - Wei Wang
- School of Life Science, Shanxi University, Taiyuan, Shanxi 030006, China
| | - Yifan Liu
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
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29
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Kriz AJ, Colognori D, Sunwoo H, Nabet B, Lee JT. Balancing cohesin eviction and retention prevents aberrant chromosomal interactions, Polycomb-mediated repression, and X-inactivation. Mol Cell 2021; 81:1970-1987.e9. [PMID: 33725485 PMCID: PMC8106664 DOI: 10.1016/j.molcel.2021.02.031] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 12/18/2020] [Accepted: 02/22/2021] [Indexed: 12/17/2022]
Abstract
Depletion of architectural factors globally alters chromatin structure but only modestly affects gene expression. We revisit the structure-function relationship using the inactive X chromosome (Xi) as a model. We investigate cohesin imbalances by forcing its depletion or retention using degron-tagged RAD21 (cohesin subunit) or WAPL (cohesin release factor). Cohesin loss disrupts the Xi superstructure, unveiling superloops between escapee genes with minimal effect on gene repression. By contrast, forced cohesin retention markedly affects Xi superstructure, compromises spreading of Xist RNA-Polycomb complexes, and attenuates Xi silencing. Effects are greatest at distal chromosomal ends, where looping contacts with the Xist locus are weakened. Surprisingly, cohesin loss creates an Xi superloop, and cohesin retention creates Xi megadomains on the active X chromosome. Across the genome, a proper cohesin balance protects against aberrant inter-chromosomal interactions and tempers Polycomb-mediated repression. We conclude that a balance of cohesin eviction and retention regulates X inactivation and inter-chromosomal interactions across the genome.
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Affiliation(s)
- Andrea J Kriz
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - David Colognori
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - Hongjae Sunwoo
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA
| | - Behnam Nabet
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
| | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
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30
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Balas MM, Hartwick EW, Barrington C, Roberts JT, Wu SK, Bettcher R, Griffin AM, Kieft JS, Johnson AM. Establishing RNA-RNA interactions remodels lncRNA structure and promotes PRC2 activity. SCIENCE ADVANCES 2021; 7:7/16/eabc9191. [PMID: 33853770 PMCID: PMC8046370 DOI: 10.1126/sciadv.abc9191] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 02/24/2021] [Indexed: 05/03/2023]
Abstract
Human Polycomb Repressive Complex 2 (PRC2) catalysis of histone H3 lysine 27 methylation at certain loci depends on long noncoding RNAs (lncRNAs). Yet, in apparent contradiction, RNA is a potent catalytic inhibitor of PRC2. Here, we show that intermolecular RNA-RNA interactions between the lncRNA HOTAIR and its targets can relieve RNA inhibition of PRC2. RNA bridging is promoted by heterogeneous nuclear ribonucleoprotein B1, which uses multiple protein domains to bind HOTAIR regions via multivalent protein-RNA interactions. Chemical probing demonstrates that establishing RNA-RNA interactions changes HOTAIR structure. Genome-wide HOTAIR/PRC2 activity occurs at genes whose transcripts can make favorable RNA-RNA interactions with HOTAIR. We demonstrate that RNA-RNA matches of HOTAIR with target gene RNAs can relieve the inhibitory effect of a single lncRNA for PRC2 activity after B1 dissociation. Our work highlights an intrinsic switch that allows PRC2 activity in specific RNA contexts, which could explain how many lncRNAs work with PRC2.
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Affiliation(s)
- Maggie M Balas
- Molecular Biology Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, 12801 East 17th Ave., Aurora, CO, USA
| | - Erik W Hartwick
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, 12801 East 17th Ave., Aurora, CO, USA
| | - Chloe Barrington
- Molecular Biology Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, 12801 East 17th Ave., Aurora, CO, USA
| | - Justin T Roberts
- Molecular Biology Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Stephen K Wu
- Molecular Biology Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ryan Bettcher
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - April M Griffin
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jeffrey S Kieft
- Molecular Biology Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, 12801 East 17th Ave., Aurora, CO, USA
| | - Aaron M Johnson
- Molecular Biology Program, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- RNA Bioscience Initiative, University of Colorado Anschutz Medical Campus, 12801 East 17th Ave., Aurora, CO, USA
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31
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Ruan J, Wu M, Ye X, Zhao S, Liang J, Ye L, You Z, Zhong B. Comparative mRNA and LncRNA Analysis of the Molecular Mechanisms Associated With Low Silk Production in Bombyx mori. Front Genet 2021; 11:592128. [PMID: 33552120 PMCID: PMC7859555 DOI: 10.3389/fgene.2020.592128] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 12/18/2020] [Indexed: 01/04/2023] Open
Abstract
Naked pupa sericin and Naked pupa are two mutant strains of Bombyx mori with extremely low or no fibroin production compared to the Qiufeng and Baiyu strains, both of which exhibit very high silk fibroin production. However, the molecular mechanisms by which long non-coding RNAs regulate fibroin synthesis need further study. In this study, we performed high-throughput RNA-seq to investigate lncRNA and mRNA expression profiles in the posterior silk gland of Qiufeng, Baiyu, Nd-sD, and Nd silkworms at the third day of the 5th instar. Our efforts yielded 26,767 novel lncRNAs and 6,009 novel mRNAs, the expression levels of silk protein genes and silk gland transcription factors were decreased in Qiufeng vs. Nd-sD and Qiufeng vs. Nd, while those of many genes related to autophagy, apoptosis, RNA degradation, ubiquitin-mediated proteolysis and heat shock proteins were increased. Moreover, the expression of a large number of genes responsible for protein synthesis and secretion was significantly decreased in Nd. GO and KEGG analysis results showed that nucleotide excision repair, mRNA surveillance pathways, amino acid degradation, protein digestion and absorption, ER-associated degradation and proteasome pathways were significantly enriched for the Qiufeng vs. Nd-sD and Qiufeng vs. Nd comparisons. In conclusion, our findings contribute to the lncRNA and mRNA database of Bombyx mori, and the identified differentially expressed mRNAs and lncRNAs help to reveal the molecular mechanisms of low silk production in Nd-sD and Nd, providing new insights for improvement of silk yield and elucidation of silk mechanical properties.
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Affiliation(s)
- Jinghua Ruan
- College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Meiyu Wu
- College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Xiaogang Ye
- College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Shuo Zhao
- College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Jianshe Liang
- College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, China
| | - Lupeng Ye
- College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Zhengying You
- College of Animal Sciences, Zhejiang University, Hangzhou, China.,College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Boxiong Zhong
- College of Animal Sciences, Zhejiang University, Hangzhou, China
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32
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Epigenetic Regulation of Pulmonary Arterial Hypertension-Induced Vascular and Right Ventricular Remodeling: New Opportunities? Int J Mol Sci 2020; 21:ijms21238901. [PMID: 33255338 PMCID: PMC7727715 DOI: 10.3390/ijms21238901] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 12/11/2022] Open
Abstract
Pulmonary artery hypertension (PAH) is a rare chronic disease with high impact on patients’ quality of life and currently no available cure. PAH is characterized by constant remodeling of the pulmonary artery by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), fibroblasts (FBs) and endothelial cells (ECs). This remodeling eventually leads to increased pressure in the right ventricle (RV) and subsequent right ventricle hypertrophy (RVH) which, when left untreated, progresses into right ventricle failure (RVF). PAH can not only originate from heritable mutations, but also develop as a consequence of congenital heart disease, exposure to drugs or toxins, HIV, connective tissue disease or be idiopathic. While much attention was drawn into investigating and developing therapies related to the most well understood signaling pathways in PAH, in the last decade, a shift towards understanding the epigenetic mechanisms driving the disease occurred. In this review, we reflect on the different epigenetic regulatory factors that are associated with the pathology of RV remodeling, and on their relevance towards a better understanding of the disease and subsequently, the development of new and more efficient therapeutic strategies.
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33
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Li Y, Li X, Yang J, He Y. Natural antisense transcripts of MIR398 genes suppress microR398 processing and attenuate plant thermotolerance. Nat Commun 2020; 11:5351. [PMID: 33093449 PMCID: PMC7582911 DOI: 10.1038/s41467-020-19186-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 09/30/2020] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs (miRNAs) and natural antisense transcripts (NATs) control many biological processes and have been broadly applied for genetic manipulation of eukaryotic gene expression. Still unclear, however, are whether and how NATs regulate miRNA production. Here, we report that the cis-NATs of MIR398 genes repress the processing of their pri-miRNAs. Through genome-wide analysis of RNA sequencing data, we identify cis-NATs of MIRNA genes in Arabidopsis and Brassica. In Arabidopsis, MIR398b and MIR398c are coexpressed in vascular tissues with their antisense genes NAT398b and NAT398c, respectively. Knock down of NAT398b and NAT398c promotes miR398 processing, resulting in stronger plant thermotolerance owing to silencing of miR398-targeted genes; in contrast, their overexpression activates NAT398b and NAT398c, causing poorer thermotolerance due to the upregulation of miR398-targeted genes. Unexpectedly, overexpression of MIR398b and MIR398c activates NAT398b and NAT398c. Taken together, these results suggest that NAT398b/c repress miR398 biogenesis and attenuate plant thermotolerance via a regulatory loop. MiRNAs and natural antisense transcripts can both regulate gene expression and plant development. Here, the authors show that cis-NATs to MIR398 repress processing of pri-miR398 and that cis-NAT expression is downregulated at high temperatures, contributing to miR398 mediated thermotolerance responses.
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Affiliation(s)
- Yajie Li
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, 200032, Shanghai, China.,University of the Chinese Academy of Sciences, 100049, Beijing, China
| | - Xiaorong Li
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, 200032, Shanghai, China.,University of the Chinese Academy of Sciences, 100049, Beijing, China
| | - Jun Yang
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, 200032, Shanghai, China.
| | - Yuke He
- National Key Laboratory of Plant Molecular Genetics, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, 200032, Shanghai, China.
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34
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Aeby E, Lee HG, Lee YW, Kriz A, Del Rosario BC, Oh HJ, Boukhali M, Haas W, Lee JT. Decapping enzyme 1A breaks X-chromosome symmetry by controlling Tsix elongation and RNA turnover. Nat Cell Biol 2020; 22:1116-1129. [PMID: 32807903 PMCID: PMC12082808 DOI: 10.1038/s41556-020-0558-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 07/09/2020] [Indexed: 12/27/2022]
Abstract
How allelic asymmetry is generated remains a major unsolved problem in epigenetics. Here we model the problem using X-chromosome inactivation by developing "BioRBP", an enzymatic RNA-proteomic method that enables probing of low-abundance interactions and an allelic RNA-depletion and -tagging system. We identify messenger RNA-decapping enzyme 1A (DCP1A) as a key regulator of Tsix, a noncoding RNA implicated in allelic choice through X-chromosome pairing. DCP1A controls Tsix half-life and transcription elongation. Depleting DCP1A causes accumulation of X-X pairs and perturbs the transition to monoallelic Tsix expression required for Xist upregulation. While ablating DCP1A causes hyperpairing, forcing Tsix degradation resolves pairing and enables Xist upregulation. We link pairing to allelic partitioning of CCCTC-binding factor (CTCF) and show that tethering DCP1A to one Tsix allele is sufficient to drive monoallelic Xist expression. Thus, DCP1A flips a bistable switch for the mutually exclusive determination of active and inactive Xs.
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Affiliation(s)
- Eric Aeby
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Hun-Goo Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Yong-Woo Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Andrea Kriz
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Brian C Del Rosario
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Hyun Jung Oh
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- Department of Genetics, Harvard Medical School, Boston, MA, USA
| | - Myriam Boukhali
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Wilhelm Haas
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Jeannie T Lee
- Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
- Department of Genetics, Harvard Medical School, Boston, MA, USA.
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35
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Xist Repeats A and B Account for Two Distinct Phases of X Inactivation Establishment. Dev Cell 2020; 54:21-32.e5. [PMID: 32531209 DOI: 10.1016/j.devcel.2020.05.021] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 02/16/2020] [Accepted: 05/14/2020] [Indexed: 11/20/2022]
Abstract
X chromosome inactivation (XCI) is a global silencing mechanism by which XX and XY mammals equalize X-linked gene dosages. XCI begins with an establishment phase during which Xist RNA spreads and induces de novo heterochromatinization across a female X chromosome and is followed by a maintenance phase when multiple epigenetic pathways lock down the inactive X (Xi) state. Involvement of Polycomb repressive complexes 1 and 2 in XCI has been intensively studied but with conflicting conclusions regarding their recruitment and role in Xi silencing. Here, we reveal that establishment of XCI has two phases and reconcile the roles that Xist repeats A and B play in gene silencing and Polycomb recruitment. Repeat A initiates both processes, whereas repeat B bolsters or stabilizes them thereafter. Once established, XCI no longer requires repeat A during maintenance. These findings integrate disparate studies and present a unified view of Xist's role in Polycomb-mediated silencing.
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Yeh CF, Chang YCE, Lu CY, Hsuan CF, Chang WT, Yang KC. Expedition to the missing link: Long noncoding RNAs in cardiovascular diseases. J Biomed Sci 2020; 27:48. [PMID: 32241300 PMCID: PMC7114803 DOI: 10.1186/s12929-020-00647-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 03/27/2020] [Indexed: 12/31/2022] Open
Abstract
With the advances in deep sequencing-based transcriptome profiling technology, it is now known that human genome is transcribed more pervasively than previously thought. Up to 90% of the human DNA is transcribed, and a large proportion of the human genome is transcribed as long noncoding RNAs (lncRNAs), a heterogenous group of non-coding transcripts longer than 200 nucleotides. Emerging evidence suggests that lncRNAs are functional and contribute to the complex regulatory networks involved in cardiovascular development and diseases. In this article, we will review recent evidence on the roles of lncRNAs in the biological processes of cardiovascular development and disorders. The potential applications of lncRNAs as biomarkers and targets for therapeutics are also discussed.
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Affiliation(s)
- Chih-Fan Yeh
- Graduate Institute and Department of Pharmacology, National Taiwan University School of Medicine, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan.,Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan
| | - Yu-Chen Eugene Chang
- Graduate Institute and Department of Pharmacology, National Taiwan University School of Medicine, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan
| | - Cheng-Yuan Lu
- Graduate Institute and Department of Pharmacology, National Taiwan University School of Medicine, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan
| | - Chin-Feng Hsuan
- Division of Cardiology, Department of Internal Medicine, E-Da Dachang Hospital, Kaohsiung, Taiwan.,Department of Medicine, I-Shou University School of Medicine, Kaohsiung, Taiwan
| | - Wei-Tien Chang
- Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Chien Yang
- Graduate Institute and Department of Pharmacology, National Taiwan University School of Medicine, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan. .,Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, No.1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, Taiwan.
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Abstract
Long non-coding RNAs (lncRNAs) are regulators of cellular machinery that are commonly dysregulated in genitourinary malignancies. Accordingly, the investigation of lncRNAs is improving our understanding of genitourinary cancers, from development to progression and dissemination. lncRNAs are involved in major oncogenic events in genitourinary malignancies, including androgen receptor (AR) signalling in prostate cancer, hypoxia-inducible factor (HIF) pathway activation in renal cell carcinoma and invasiveness in bladder cancer, as well as multiple other proliferation and survival mechanisms. In line with their putative oncogenic roles, new lncRNA-based classifications are emerging as potent predictors of prognosis. In clinical practice, detection of oncogenic lncRNAs in serum or urine might enable early cancer detection, and lncRNAs might also be promising therapeutic targets for patients with genitourinary cancer. Furthermore, as predictors of sensitivity to anticancer treatments, lncRNAs could be integrated into future precision medicine strategies. Overall, lncRNAs are promising new candidates for molecular studies and for discovery of innovative biomarkers and are putative therapeutic targets in genitourinary oncology.
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Özdemir S, Altun S. Genome-wide analysis of mRNAs and lncRNAs in Mycoplasma bovis infected and non-infected bovine mammary gland tissues. Mol Cell Probes 2020; 50:101512. [PMID: 31972225 DOI: 10.1016/j.mcp.2020.101512] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 12/30/2019] [Accepted: 01/15/2020] [Indexed: 02/02/2023]
Abstract
Mycoplasma bovis (M. bovis) causes diseases such as arthritis, pneumonia, abortion, and mastitis, leading to great losses in the bovine dairy industries. RNA types such as messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs) play significant roles in regulating the immune responses triggered by bacteria. The expression profiles of mRNA and lncRNA as they occur in bovine mammary gland tissues infected with M. bovis are still not well understood. To illuminate this issue, transcription analysis of mRNA and LncRNAs were conducted on the mammary gland tissues belonging to Holstein cattle infected and not infected with M. bovis. The analysis revealed 1310 differentially expressed mRNAs and 57 differentially expressed lncRNAs in the bovine mammary gland tissues infected and not infected with M. bovis. In addition, 392 novel lncRNAs were detected, 19 of which were differentially expressed. Gene ontology analysis reveals that differentially expressed mRNAs and lncRNAs play significant roles in such vital biological pathways as metabolic pathways, T-cell receptor signaling, TGF-beta signaling, pathways in cancer, PI3K-Akt signaling, NF-kappa B signaling, mTOR signaling, and apoptosis, including in the immune response to cancer. Based on our literature review, this study is the first genome-wide lncRNA research conducted on bovine mammary gland tissues infected with M. bovis. Our results provide bovine mammary gland lncRNA and mRNA resources to understand their roles in the regulation of the immune response against the agent M. bovis in bovine mammary gland tissues.
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Affiliation(s)
- Selçuk Özdemir
- Atatürk Üniversity Faculty of Veterinary Medicine, Depertmant of Genetics, Erzurum, 25430, Turkey.
| | - Serdar Altun
- Atatürk Üniversity Faculty of Veterinary Medicine, Depertmant of Pathology, Erzurum, 25430, Turkey
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Zhao X, Xiong J, Mao F, Sheng Y, Chen X, Feng L, Dui W, Yang W, Kapusta A, Feschotte C, Coyne RS, Miao W, Gao S, Liu Y. RNAi-dependent Polycomb repression controls transposable elements in Tetrahymena. Genes Dev 2019; 33:348-364. [PMID: 30808657 PMCID: PMC6411011 DOI: 10.1101/gad.320796.118] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 01/02/2019] [Indexed: 12/30/2022]
Abstract
RNAi and Polycomb repression play evolutionarily conserved and often coordinated roles in transcriptional silencing. Here, we show that, in the protozoan Tetrahymena thermophila, germline-specific internally eliminated sequences (IESs)-many related to transposable elements (TEs)-become transcriptionally activated in mutants deficient in the RNAi-dependent Polycomb repression pathway. Germline TE mobilization also dramatically increases in these mutants. The transition from noncoding RNA (ncRNA) to mRNA production accompanies transcriptional activation of TE-related sequences and vice versa for transcriptional silencing. The balance between ncRNA and mRNA production is potentially affected by cotranscriptional processing as well as RNAi and Polycomb repression. We posit that interplay between RNAi and Polycomb repression is a widely conserved phenomenon, whose ancestral role is epigenetic silencing of TEs.
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Affiliation(s)
- Xiaolu Zhao
- Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
- Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao 266003, China
| | - Jie Xiong
- Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Fengbiao Mao
- Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Yalan Sheng
- Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao 266003, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China
| | - Xiao Chen
- Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
- Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao 266003, China
| | - Lifang Feng
- Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Wen Dui
- Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Wentao Yang
- Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Aurélie Kapusta
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA
| | - Cédric Feschotte
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14850, USA
| | - Robert S Coyne
- J. Craig Venter Institute, Rockville, Maryland 20850, USA
| | - Wei Miao
- Key Laboratory of Aquatic Biodiversity and Conservation, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Shan Gao
- Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao 266003, China
- Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China
| | - Yifan Liu
- Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
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Colognori D, Sunwoo H, Kriz AJ, Wang CY, Lee JT. Xist Deletional Analysis Reveals an Interdependency between Xist RNA and Polycomb Complexes for Spreading along the Inactive X. Mol Cell 2019; 74:101-117.e10. [PMID: 30827740 DOI: 10.1016/j.molcel.2019.01.015] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 11/21/2018] [Accepted: 01/10/2019] [Indexed: 12/16/2022]
Abstract
During X-inactivation, Xist RNA spreads along an entire chromosome to establish silencing. However, the mechanism and functional RNA elements involved in spreading remain undefined. By performing a comprehensive endogenous Xist deletion screen, we identify Repeat B as crucial for spreading Xist and maintaining Polycomb repressive complexes 1 and 2 (PRC1/PRC2) along the inactive X (Xi). Unexpectedly, spreading of these three factors is inextricably linked. Deleting Repeat B or its direct binding partner, HNRNPK, compromises recruitment of PRC1 and PRC2. In turn, ablating PRC1 or PRC2 impairs Xist spreading. Therefore, Xist and Polycomb complexes require each other to propagate along the Xi, suggesting a positive feedback mechanism between RNA initiator and protein effectors. Perturbing Xist/Polycomb spreading causes failure of de novo Xi silencing, with partial compensatory downregulation of the active X, and also disrupts topological Xi reconfiguration. Thus, Repeat B is a multifunctional element that integrates interdependent Xist/Polycomb spreading, silencing, and changes in chromosome architecture.
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Affiliation(s)
- David Colognori
- Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Hongjae Sunwoo
- Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Andrea J Kriz
- Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Chen-Yu Wang
- Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
| | - Jeannie T Lee
- Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
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Liu H, Wang R, Mao B, Zhao B, Wang J. Identification of lncRNAs involved in rice ovule development and female gametophyte abortion by genome-wide screening and functional analysis. BMC Genomics 2019; 20:90. [PMID: 30691391 PMCID: PMC6348626 DOI: 10.1186/s12864-019-5442-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 01/09/2019] [Indexed: 11/15/2022] Open
Abstract
Background As important female reproductive tissues, the rice (Oryza sativa L.) ovule and female gametophyte is significant in terms of their fertility. Long noncoding RNAs (lncRNAs) play important and wide-ranging roles in the growth and development of plants and have become a major research focus in recent years. Therefore, we explored the characterization and expression change of lncRNAs during ovule development and female gametophytic abortion. Results In our study, whole-transcriptome strand-specific RNA sequencing (ssRNA-seq) was performed in the ovules of a high-frequency female-sterile rice line (fsv1) and a wild-type rice line (Gui99) at the megaspore mother cell meiosis stage (stage 1), functional megaspore mitosis stage (stage 2) and female gametophyte mature stage (stage 3). By comparing two rice lines, we identified 152, 233, and 197 differentially expressed lncRNAs at the three ovule developmental stages. Functional analysis of the coherent target genes of these differentially expressed lncRNAs indicated that many lncRNAs participate in multiple pathways such as hormone and cellular metabolism and signal transduction. Moreover, there were many differentially expressed lncRNAs acting as the precursors of some miRNAs that are involved in the development of ovules and female gametophytes. In addition, we have found that lncRNAs can act as decoys, competing with mRNAs for binding to miRNAs to maintain the normal expression of genes related to ovule and female gametophyte development. Conclusion These results provide important clues for elucidating the female gametophyte abortion mechanism in rice. This study also expands our understanding about the biological functions of lncRNAs and the annotation of the rice genome. Electronic supplementary material The online version of this article (10.1186/s12864-019-5442-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Helian Liu
- State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Ruihua Wang
- State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, 430072, China
| | - Bigang Mao
- State Key Laboratory of Hybrid Rice, Hunan Hybrid Rice Research Center, Changsha, 410125, China
| | - Bingran Zhao
- State Key Laboratory of Hybrid Rice, Hunan Hybrid Rice Research Center, Changsha, 410125, China.
| | - Jianbo Wang
- State Key Laboratory of Hybrid Rice, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
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Del Rosario BC, Kriz AJ, Del Rosario AM, Anselmo A, Fry CJ, White FM, Sadreyev RI, Lee JT. Exploration of CTCF post-translation modifications uncovers Serine-224 phosphorylation by PLK1 at pericentric regions during the G2/M transition. eLife 2019; 8:e42341. [PMID: 30676316 PMCID: PMC6361588 DOI: 10.7554/elife.42341] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 01/23/2019] [Indexed: 01/05/2023] Open
Abstract
The zinc finger CCCTC-binding protein (CTCF) carries out many functions in the cell. Although previous studies sought to explain CTCF multivalency based on sequence composition of binding sites, few examined how CTCF post-translational modification (PTM) could contribute to function. Here, we performed CTCF mass spectrometry, identified a novel phosphorylation site at Serine 224 (Ser224-P), and demonstrate that phosphorylation is carried out by Polo-like kinase 1 (PLK1). CTCF Ser224-P is chromatin-associated, mapping to at least a subset of known CTCF sites. CTCF Ser224-P accumulates during the G2/M transition of the cell cycle and is enriched at pericentric regions. The phospho-obviation mutant, S224A, appeared normal. However, the phospho-mimic mutant, S224E, is detrimental to mouse embryonic stem cell colonies. While ploidy and chromatin architecture appear unaffected, S224E mutants differentially express hundreds of genes, including p53 and p21. We have thus identified a new CTCF PTM and provided evidence of biological function.
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Affiliation(s)
- Brian C Del Rosario
- Department of Molecular BiologyHoward Hughes Medical Institute, Massachusetts General HospitalBostonUnited States
- Department of GeneticsHarvard Medical SchoolBostonUnited States
| | - Andrea J Kriz
- Department of Molecular BiologyHoward Hughes Medical Institute, Massachusetts General HospitalBostonUnited States
- Department of GeneticsHarvard Medical SchoolBostonUnited States
| | - Amanda M Del Rosario
- Koch Institute for Integrative Cancer ResearchMassachusetts Institute of TechnologyCambridgeUnited States
| | - Anthony Anselmo
- Department of Molecular BiologyMassachusetts General HospitalBostonUnited States
| | | | - Forest M White
- Koch Institute for Integrative Cancer ResearchMassachusetts Institute of TechnologyCambridgeUnited States
| | - Ruslan I Sadreyev
- Department of Molecular BiologyMassachusetts General HospitalBostonUnited States
| | - Jeannie T Lee
- Department of Molecular BiologyHoward Hughes Medical Institute, Massachusetts General HospitalBostonUnited States
- Department of GeneticsHarvard Medical SchoolBostonUnited States
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Megadomains and superloops form dynamically but are dispensable for X-chromosome inactivation and gene escape. Nat Commun 2018; 9:5004. [PMID: 30479398 PMCID: PMC6258728 DOI: 10.1038/s41467-018-07446-w] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 10/24/2018] [Indexed: 01/17/2023] Open
Abstract
The mammalian inactive X-chromosome (Xi) is structurally distinct from all other chromosomes and serves as a model for how the 3D genome is organized. The Xi shows weakened topologically associated domains and is instead organized into megadomains and superloops directed by the noncoding loci, Dxz4 and Firre. Their functional significance is presently unclear, though one study suggests that they permit Xi genes to escape silencing. Here, we find that megadomains do not precede Xist expression or Xi gene silencing. Deleting Dxz4 disrupts the sharp megadomain border, whereas deleting Firre weakens intra-megadomain interactions. However, deleting Dxz4 and/or Firre has no impact on Xi silencing and gene escape. Nor does it affect Xi nuclear localization, stability, or H3K27 methylation. Additionally, ectopic integration of Dxz4 and Xist is not sufficient to form megadomains on autosomes. We conclude that Dxz4 and megadomains are dispensable for Xi silencing and escape from X-inactivation. The mammalian inactive X-chromosome (Xi) is organized into megadomains and superloops directed by the noncoding loci, Dxz4 and Firre. Here the authors provide evidence that megadomains do not precede Xist expression or Xi gene silencing, and suggest that Dxz4, Firre, and megadomains are dispensable for Xi silencing and escape from X-inactivation.
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44
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Zhao CN, Mao YM, Liu LN, Li XM, Wang DG, Pan HF. Emerging role of lncRNAs in systemic lupus erythematosus. Biomed Pharmacother 2018; 106:584-592. [DOI: 10.1016/j.biopha.2018.06.175] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 06/26/2018] [Accepted: 06/29/2018] [Indexed: 12/13/2022] Open
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45
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Zheng X, Ning C, Zhao P, Feng W, Jin Y, Zhou L, Yu Y, Liu J. Integrated analysis of long noncoding RNA and mRNA expression profiles reveals the potential role of long noncoding RNA in different bovine lactation stages. J Dairy Sci 2018; 101:11061-11073. [PMID: 30268606 DOI: 10.3168/jds.2018-14900] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 08/20/2018] [Indexed: 12/12/2022]
Abstract
Long noncoding RNA (lncRNA) play a critical role in mammary development and breast cancer biology. Despite their important role in the mammary gland, little is known of the roles of lncRNA in bovine lactation, particularly regarding the molecular processes underlying it. To characterize the role of lncRNA in bovine lactation, 4 samples of Holstein cow mammary gland tissue at peak and late lactation stages were examined after biopsy. We then profiled the transcriptome of the mammary gland using RNA sequencing technology. Further, functional lncRNA-mRNA coexpression pairs were constructed to infer the function of lncRNA using a generalized linear model, followed by gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. More than 1,000 putative lncRNA were identified, 117 of which were differentially expressed between peak and late lactation stages. Bovine lncRNA were shorter, with fewer exon numbers, and expressed at significantly lower levels than protein-coding genes. Seventy-two differentially expressed (DE) lncRNA were coexpressed with 340 different protein-coding genes. The KEGG pathway analysis showed that target mRNA for DE lncRNA were mainly related to lipid and glucose metabolism, including the peroxisome proliferator-activated receptors and 5' adenosine monophosphate-activated protein kinase signaling pathways. Further bioinformatics and integrative analyses revealed that 12 DE lncRNA potentially played important roles in bovine lactation. Our findings provide a valuable resource for future bovine transcriptome studies, facilitate the understanding of bovine lactation biology, and offer functional information for cattle lactation.
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Affiliation(s)
- X Zheng
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - C Ning
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - P Zhao
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - W Feng
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Y Jin
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - L Zhou
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Y Yu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - J Liu
- National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China.
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Yu H, Rong L. Emerging role of long non-coding RNA in the development of gastric cancer. World J Gastrointest Oncol 2018; 10:260-270. [PMID: 30254721 PMCID: PMC6147769 DOI: 10.4251/wjgo.v10.i9.260] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/14/2018] [Accepted: 06/27/2018] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is a common, worldwide malignancy and has a poor prognosis due to late diagnosis. Long non-coding RNAs (lncRNAs) are a significant subtype of RNA molecules with a length longer than 200 nucleotides (nt) that rarely encode proteins. In recent decades, deregulation of lncRNAs has been shown to be involved in tumorigenesis and tumor progression in various human carcinomas, including gastric cancer. Accumulating evidence has shown that some lncRNAs may function as diagnostic biomarkers or therapeutic targets for gastric cancer. Thus, exploring the specific functions of lncRNAs will help both gain a better understanding of the pathogenesis and develop novel treatments for gastric cancer. In this review, we highlight the expression and functional roles of lncRNAs in gastric cancer, and analyze the potential applications of lncRNAs as diagnostic markers and therapeutic targets.
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Affiliation(s)
- Hang Yu
- Department of Endoscopic Center, Peking University First Hospital, Beijing 100034, China
| | - Long Rong
- Department of Endoscopic Center, Peking University First Hospital, Beijing 100034, China
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Chen X, Zhu Z, Yu F, Huang J, Jia R, Pan J. Effect of shRNA-mediated Xist knockdown on the quality of porcine parthenogenetic embryos. Dev Dyn 2018; 248:140-148. [PMID: 30055068 DOI: 10.1002/dvdy.24660] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 06/27/2018] [Accepted: 07/13/2018] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Parthenogenetically activated oocytes exhibit poor embryo development and lower total numbers of cells per blastocyst accompanied by abnormally increased expression of Xist, a long noncoding RNA that plays an important role in triggering X chromosome inactivation during embryogenesis. RESULTS To investigate whether knockdown of Xist influences parthenogenetic development in pigs. We developed an anti-Xist short hairpin RNA (shRNA) vector, which can significantly inhibit Xist expression for at least seven days when injected at 12-13 hr after parthenogenetic activation. Embryonic cleavage, blastocyst formation, and total blastocyst cell numbers were compared during the blastocyst stage, as well as the expression of an X-linked gene and three pluripotent transcription factors. Knockdown of Xist significantly increases the total blastocyst cell number, but does not influence the rate of embryo cleavage and blastocyst formation. The expressions of Sox2, Nanog, and Oct4 were also significantly improved in the injected embryos compared with the control at the blastocyst stage, but the Foxp3 expression level was not increased significantly. CONCLUSIONS The present study provides valuable information for understanding the role of Xist in parthenogenesis and presents a new approach for improving the quality of porcine parthenogenetic embryos. Developmental Dynamics 248:140-148, 2019. © 2018 Wiley Periodicals, Inc.
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Affiliation(s)
- Xiaoyu Chen
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agriculture Science, Hangzhou, Zhejiang, P.R. China
| | - Zhiwei Zhu
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agriculture Science, Hangzhou, Zhejiang, P.R. China
| | - Fuxian Yu
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agriculture Science, Hangzhou, Zhejiang, P.R. China
| | - Jing Huang
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agriculture Science, Hangzhou, Zhejiang, P.R. China
| | - Ruoxin Jia
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agriculture Science, Hangzhou, Zhejiang, P.R. China
| | - Jianzhi Pan
- Institute of Animal Husbandry and Veterinary Science, Zhejiang Academy of Agriculture Science, Hangzhou, Zhejiang, P.R. China
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SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X. Cell 2018; 174:406-421.e25. [PMID: 29887375 DOI: 10.1016/j.cell.2018.05.007] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 03/19/2018] [Accepted: 05/02/2018] [Indexed: 12/22/2022]
Abstract
Mammalian chromosomes are partitioned into A/B compartments and topologically associated domains (TADs). The inactive X (Xi) chromosome, however, adopts a distinct conformation without evident compartments or TADs. Here, through exploration of an architectural protein, structural-maintenance-of-chromosomes hinge domain containing 1 (SMCHD1), we probe how the Xi is reconfigured during X chromosome inactivation. A/B compartments are first fused into "S1" and "S2" compartments, coinciding with Xist spreading into gene-rich domains. SMCHD1 then binds S1/S2 compartments and merges them to create a compartment-less architecture. Contrary to current views, TADs remain on the Xi but in an attenuated state. Ablating SMCHD1 results in a persistent S1/S2 organization and strengthening of TADs. Furthermore, loss of SMCHD1 causes regional defects in Xist spreading and erosion of heterochromatic silencing. We present a stepwise model for Xi folding, where SMCHD1 attenuates a hidden layer of Xi architecture to facilitate Xist spreading.
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Liu P, Jin L, Zhao L, Long K, Song Y, Tang Q, Ma J, Wang X, Tang G, Jiang Y, Zhu L, Li X, Li M. Identification of a novel antisense long non-coding RNA PLA2G16-AS that regulates the expression of PLA2G16 in pigs. Gene 2018; 671:78-84. [PMID: 29860067 DOI: 10.1016/j.gene.2018.05.114] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 05/28/2018] [Accepted: 05/30/2018] [Indexed: 02/06/2023]
Abstract
Natural antisense transcripts (NATs) are widely present in mammalian genomes and act as pivotal regulator molecules to control gene expression. However, studies on the NATs of pigs are relatively rare. Here, we identified a novel antisense transcript, designated PLA2G16-AS, transcribed from the phospholipase A2 group XVI locus (PLA2G16) in the porcine genome, which is a well-known regulatory molecule of fat deposition. PLA2G16-AS and PLA2G16 were dominantly expressed in porcine adipose tissue, and were differentially expressed between Tibetan pigs and Rongchang pigs. In addition, PLA2G16-AS has a weak sequence conservation among different vertebrates. PLA2G16-AS was also shown to form an RNA-RNA duplex with PLA2G16, and to regulate PLA2G16 expression at the mRNA level. Moreover, the overexpression of PLA2G16-AS increased the stability of PLA2G16 mRNA in porcine cells. We envision that our findings of a NAT for a regulatory gene associated with lipolysis might further our understanding of the molecular regulation of fat deposition.
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Affiliation(s)
- Pengliang Liu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Long Jin
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Lirui Zhao
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Keren Long
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Yang Song
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Qianzi Tang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Jideng Ma
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Xun Wang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Guoqing Tang
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Yanzhi Jiang
- Department of Zoology, College of Life Science, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Li Zhu
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Xuewei Li
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China
| | - Mingzhou Li
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, PR China.
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Knockdown CRNDE alleviates LPS-induced inflammation injury via FOXM1 in WI-38 cells. Biomed Pharmacother 2018; 103:1678-1687. [PMID: 29864958 DOI: 10.1016/j.biopha.2018.04.192] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 04/25/2018] [Accepted: 04/29/2018] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Pneumonia is the leading global cause of mortality and morbidity in children and elderly people worldwide. The lncRNA colorectal neoplasia differentially expressed (CRNDE) plays an important role in the human development and disease progression. The present study was aimed to investigate the effect of CRNDE on LPS-induced injuries in WI-38 cells and explore the potential mechanism. METHODS WI-38 cells were treated with LPS to induce injuries. The expression of CRNDE and FOXM1 in WI-38 cells were altered by transient transfection assay. Cell viability was measured by CCK-8 assay and cell apoptosis was detected by flow cytometry assay and western blot. The levels of inflammatory cytokines were assessed by ELISA and western blot. Furthermore, western blot analysis was performed to detect the expression levels of NF-κB and JAK/STAT pathway-related proteins. RESULTS LPS exposure induced cell injuries and increased CRNDE expression in WI-38 cells. CRNDE overexpression enhanced cell injuries in WI-38 cells with significantly reducing cell viability, increasing cell apoptosis and inflammatory cytokines levels. In addition, CRNDE overexpression further activated the NF-κB and JAK/STAT pathways in LPS-injured WI-38 cells. Inversely, opposite results were observed in CRNDE inhibition treatment group. Interestingly, FOXM1 was up-regulated by CRNDE and FOXM1 silence blocked the effect of CRNDE overexpression in cell apoptosis, inflammation and activation of NF-κB and JAK/STAT signaling pathways. CONCLUSION This study demonstrated that CRNDE overexpression accelerated LPS-induced apoptosis and inflammation via up-regulation of FOXM1 in WI-38 cells.
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