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1
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Ou L, Liu H, Peng C, Zou Y, Jia J, Li H, Feng Z, Zhang G, Yao M. Helicobacter pylori infection facilitates cell migration and potentially impact clinical outcomes in gastric cancer. Heliyon 2024; 10:e37046. [PMID: 39286209 PMCID: PMC11402937 DOI: 10.1016/j.heliyon.2024.e37046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 08/23/2024] [Accepted: 08/27/2024] [Indexed: 09/19/2024] Open
Abstract
Gastric cancer is a significant health concern worldwide. Helicobacter pylori (HP) infection is associated with gastric cancer risk, but differences between HP-infected and HP-free gastric cancer have not been studied sufficiently. The objective of this study was to investigate the effects of HP infection on the viability and migration of gastric cancer cells and identify potential underlying genetic mechanisms as well as their clinical relevance. Cell counting kit-8, lactate dehydrogenase, wound healing, and transwell assay were applied in the infection model of multiple clones of HP and multiple gastric cancer cell lines. Genes related to HP infection were identified using bioinformatics analysis and subsequently validated using real-time quantitative PCR. The association of these genes with immunity and drug sensitivity of gastric cancer was analyzed. Results showed that HP has no significant impact on viability but increases the migration of gastric cancer cells. We identified 1405 HP-upregulated genes, with their enriched terms relating to cell migration, drug, and immunity. Among these genes, the 82 genes associated with survival showed a significant impact on gastric cancer in consensus clustering and LASSO prognostic model. The top 10 hub HP-associated genes were further identified, and 7 of them were validated in HP-infected cells using real-time quantitative PCR, including ERBB4, DNER, BRINP2, KCTD16, MAPK4, THPO, and VSTM2L. The overexpression experiment showed that KCTD16 medicated the effect of HP on gastric cancer migration. Our findings suggest that HP infection may enhance the migratory potential of gastric cancer cells and these genes might be associated with immunity and drug sensitivity of gastric cancer. In human subjects with gastric cancer, HP presence in tumors may affect migration, immunity, and drug sensitivity.
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Affiliation(s)
- Ling Ou
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Hengrui Liu
- Cancer Institute, Jinan University, Guangzhou, China
- Tianjin Yinuo Biomedical Co., Ltd, Tianjin, China
| | - Chang Peng
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Yuanjing Zou
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
| | - Junwei Jia
- International Pharmaceutical Engineering Lab of Shandong Province, Feixian, 273400, Shandong, China
| | - Hui Li
- International Pharmaceutical Engineering Lab of Shandong Province, Feixian, 273400, Shandong, China
| | - Zhong Feng
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
- International Pharmaceutical Engineering Lab of Shandong Province, Feixian, 273400, Shandong, China
| | - Guimin Zhang
- Lunan Pharmaceutical Group Co., Ltd, Linyi, 276000, Shandong, China
| | - Meicun Yao
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China
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2
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Mironova E, Molinas S, Pozo VD, Bandyopadhyay AM, Lai Z, Kurmashev D, Schneider EL, Santi DV, Chen Y, Kurmasheva RT. Synergistic Antitumor Activity of Talazoparib and Temozolomide in Malignant Rhabdoid Tumors. Cancers (Basel) 2024; 16:2041. [PMID: 38893160 PMCID: PMC11171327 DOI: 10.3390/cancers16112041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 05/20/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Malignant rhabdoid tumors (MRTs) are among the most aggressive and treatment-resistant malignancies affecting infants, originating in the kidney, brain, liver, and soft tissues. The 5-year event-free survival rate for these cancers is a mere 20%. In nearly all cases of MRT, the SMARCB1 gene (occasionally SMARCA4)-a pivotal component of the SWI/SNF chromatin remodeling complex-is homozygously deleted, although the precise etiology of these tumors remains unknown. While young patients with localized MRT generally show improved outcomes, especially those who are older and have early-stage disease, the overall prognosis remains poor despite optimal standard treatments. This highlights the urgent need for more effective treatment strategies. We investigated the antitumor activity of a PARP1 inhibitor (talazoparib, TLZ) combined with a DNA alkylating agent (temozolomide, TMZ) in MRT xenograft models. PARP1 is a widely targeted molecule in cancer treatment and, beyond its role in DNA repair, it participates in transcriptional regulation by recruiting chromatin remodeling complexes to modulate DNA accessibility for RNA polymerases. To widen the therapeutic window of the drug combination, we employed PEGylated TLZ (PEG~TLZ), which has been reported to reduce systemic toxicity through slow drug release. Remarkably, our findings indicate that five out of six MRT xenografts exhibited an objective response to PEG~TLZ+TMZ therapy. Significantly, the loss of SMARCB1 was found to confer a protective effect, correlating with higher expression levels of DNA damage and repair proteins in SMARCB1-deficient MRT cells. Additionally, we identified MGMT as a potential biomarker indicative of in vivo MRT response to PEG~TLZ+TMZ therapy. Moreover, our analysis revealed alterations in signaling pathways associated with the observed antitumor efficacy. This study presents a novel and efficacious therapeutic approach for MRT, along with a promising candidate biomarker for predicting tumor response.
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Affiliation(s)
- Elena Mironova
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Sebastian Molinas
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Vanessa Del Pozo
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Abhik M. Bandyopadhyay
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Zhao Lai
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Dias Kurmashev
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
| | | | | | - Yidong Chen
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
- Department of Population Health Sciences, University of Texas Health Science Center, San Antonio, TX 78229, USA
| | - Raushan T. Kurmasheva
- Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA
- Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA
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3
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Griffin EN, Jucius T, Sim SE, Harris BS, Heinz S, Ackerman SL. RREB1 regulates neuronal proteostasis and the microtubule network. SCIENCE ADVANCES 2024; 10:eadh3929. [PMID: 38198538 PMCID: PMC10780896 DOI: 10.1126/sciadv.adh3929] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 12/12/2023] [Indexed: 01/12/2024]
Abstract
Transcription factors play vital roles in neuron development; however, little is known about the role of these proteins in maintaining neuronal homeostasis. Here, we show that the transcription factor RREB1 (Ras-responsive element-binding protein 1) is essential for neuron survival in the mammalian brain. A spontaneous mouse mutation causing loss of a nervous system-enriched Rreb1 transcript is associated with progressive loss of cerebellar Purkinje cells and ataxia. Analysis of chromatin immunoprecipitation and sequencing, along with RNA sequencing data revealed dysregulation of RREB1 targets associated with the microtubule cytoskeleton. In agreement with the known role of microtubules in dendritic development, dendritic complexity was disrupted in Rreb1-deficient neurons. Analysis of sequencing data also suggested that RREB1 plays a role in the endomembrane system. Mutant Purkinje cells had fewer numbers of autophagosomes and lysosomes and contained P62- and ubiquitin-positive inclusions. Together, these studies demonstrate that RREB1 functions to maintain the microtubule network and proteostasis in mammalian neurons.
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Affiliation(s)
- Emily N. Griffin
- Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, Department of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Thomas Jucius
- Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, Department of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Su-Eon Sim
- Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, Department of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA
| | | | - Sven Heinz
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Susan L. Ackerman
- Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, Department of Neurobiology, University of California, San Diego, La Jolla, CA 92093, USA
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4
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Kang Y, Xu X, Liu J. System Analysis Based on Pancreatic Cancer Progression Identifies BRINP2 as a Novel Prognostic Biomarker. Crit Rev Eukaryot Gene Expr 2023; 33:1-16. [PMID: 37602449 DOI: 10.1615/critreveukaryotgeneexpr.2023048337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2023]
Abstract
Pancreatic adenocarcinoma (PAAD) is a malignant tumor of the digestive system, which develops rapidly and has no obvious early symptoms. This study aims to discover the biomarkers associated with PAAD development. We obtained RNA expression of PAAD patient samples and corresponding clinical data from The cancer genome atlas (TCGA), and screened out BMP/RA-inducible neural-specific protein 2 (BRINP2) gene which is highly associated with PAAD severity. Then, gene ontology (GO) enrichment, Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis and single-sample gene set enrichment analysis (ssGSEA) analysis were performed to explore the biological functions of BRINP2. Subsequently, long non-coding RNA (lncRNAs) associated with BRINP2 were screened out via correlation analysis, and Cox regression analysis and least absolute shrinkage selection operator (LASSO) regression analysis were used to construct the risk prediction model. We further validated the expression level of BRINP2 and its associated lncRNAs in BRINP2-associated lncRNAs prognostic model in vitro. We proposed that BRINP2 might be correlated to the tumor immune microenvironment and could also be used as a biomarker for PAAD progression. GO enrichment analysis and KEGG pathway analysis showed that the prognostic model was highly correlated to immune microenvironment-related pathways. Additionally, we established a BRINP2-associated lncRNAs prognostic model consisting of three lncRNAs. We validated the expression trends of BRINP2 and its associated lncRNAs in BRINP2-associated lncRNAs prognostic model in PAAD cells with various severity of metastatic potential using the quantitative real-time PCR (qRT-PCR). Meanwhile, pRRophetic R package was employed to predict potential therapeutic drugs for BRINP2-associated lncRNAs prognostic model of PAAD. The results suggest that BRINP2 can be used as a novel prognostic biomarker for PAAD.
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Affiliation(s)
- Yixing Kang
- Department of Clinical Medicine, Weifang Medical University, Weifang 261031, China
| | - Xiangwen Xu
- Department of Plastic and Reconstructive Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Jikui Liu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
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5
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Gürünlüoğlu K, Dündar M, Unver T, Akpınar N, Gokce IK, Gürünlüoğlu S, Demircan M, Koc A. Global gene expression profiling in congenital diaphragmatic hernia (CDH) patients. Funct Integr Genomics 2022; 22:359-369. [PMID: 35260975 DOI: 10.1007/s10142-022-00837-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 02/03/2023]
Abstract
Congenital diaphragmatic hernia (CDH) is an anomaly characterized by a defect in the diaphragm, leading to the passage of intra-abdominal organs into the thoracic cavity. Herein, the presented work analyzes the global gene expression profiles in nine CDH and one healthy newborn. All of the patients had left posterolateral (Bochdalek) diaphragmatic hernia, operated via an abdominal approach, and stomach and bowels in the thorax cavity. Some patients also had additional anomalies. A total of 560 differentially regulated genes were measured. Among them, 11 genes showed significant changes in expression associated with lung tissue, vascular structure development, and vitamin A metabolism, which are typical ontologies related to CDH etiology. Among them, SLC25A24 and RAB3IL1 are involved in angiogenesis, HIF1A and FOXC2-AS1 are related with the alveolus, MAGI2-AS3 is associated with the diaphragm, LHX4 and DHH are linked with the lung, and BRINP1, FZD9, WNT4, and BLOC1S1-RDH5 are involved in retinol. Besides, the expression levels of some previously claimed genes with CDH etiology also showed diverse expression patterns in different patients. All these indicated that CDH is a complex, multigenic anomaly, requiring holistic approaches for its elucidation.
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Affiliation(s)
- Kubilay Gürünlüoğlu
- Department of Pediatric Surgery, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Muhammed Dündar
- Department of Medical Genetics, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Turgay Unver
- Ficus Biotechnology Ostim OSB Mah, Inonu University, 100. Yıl Blv. No:55 Yenimahalle, Malatya, Turkey
| | - Necmettin Akpınar
- Department of Pediatric Surgery, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Ismail Kürşad Gokce
- Department of Pediatrics and Division of Neonatology, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Semra Gürünlüoğlu
- Department of Pathology, Malatya Education and Research Hospital, Malatya, Turkey
| | - Mehmet Demircan
- Department of Pediatric Surgery, Faculty of Medicine, Inonu University, Malatya, Turkey
| | - Ahmet Koc
- Department of Medical Genetics, Faculty of Medicine, Inonu University, Malatya, Turkey.
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6
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Nagashima S, Ito N, Kobayashi R, Shiiba I, Shimura H, Fukuda T, Hagihara H, Miyakawa T, Inatome R, Yanagi S. Forebrain-specific deficiency of the GTPase CRAG/Centaurin-γ3 leads to immature dentate gyri and hyperactivity in mice. J Biol Chem 2021; 296:100620. [PMID: 33811862 PMCID: PMC8099661 DOI: 10.1016/j.jbc.2021.100620] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 03/25/2021] [Accepted: 03/30/2021] [Indexed: 11/26/2022] Open
Abstract
Mouse models of various neuropsychiatric disorders, such as schizophrenia, often display an immature dentate gyrus, characterized by increased numbers of immature neurons and neuronal progenitors and a dearth of mature neurons. We previously demonstrated that the CRMP5-associated GTPase (CRAG), a short splice variant of Centaurin-γ3/AGAP3, is highly expressed in the dentate gyrus. CRAG promotes cell survival and antioxidant defense by inducing the activation of serum response factors at promyelocytic leukemia protein bodies, which are nuclear stress-responsive domains, during neuronal development. However, the physiological role of CRAG in neuronal development remains unknown. Here, we analyzed the role of CRAG using dorsal forebrain-specific CRAG/Centaurin-γ3 knockout mice. The mice revealed maturational abnormality of the hippocampal granule cells, including increased doublecortin-positive immature neurons and decreased calbindin-positive mature neurons, a typical phenotype of immature dentate gyri. Furthermore, the mice displayed hyperactivity in the open-field test, a common measure of exploratory behavior, suggesting that these mice may serve as a novel model for neuropsychiatric disorder associated with hyperactivity. Thus, we conclude that CRAG is required for the maturation of neurons in the dentate gyrus, raising the possibility that its deficiency might promote the development of psychiatric disorders in humans.
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Affiliation(s)
- Shun Nagashima
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
| | - Naoki Ito
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; Laboratory of Molecular Biochemistry, Department of Life Science, Faculty of Science, Gakushuin University, Toshima-ku, Tokyo, Japan
| | - Reiki Kobayashi
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Isshin Shiiba
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; Laboratory of Molecular Biochemistry, Department of Life Science, Faculty of Science, Gakushuin University, Toshima-ku, Tokyo, Japan
| | - Hiroki Shimura
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Toshifumi Fukuda
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan
| | - Hideo Hagihara
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan
| | - Tsuyoshi Miyakawa
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan
| | - Ryoko Inatome
- Laboratory of Molecular Biochemistry, Department of Life Science, Faculty of Science, Gakushuin University, Toshima-ku, Tokyo, Japan
| | - Shigeru Yanagi
- Laboratory of Molecular Biochemistry, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; Laboratory of Molecular Biochemistry, Department of Life Science, Faculty of Science, Gakushuin University, Toshima-ku, Tokyo, Japan.
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7
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Bayly-Jones C, Pang SS, Spicer BA, Whisstock JC, Dunstone MA. Ancient but Not Forgotten: New Insights Into MPEG1, a Macrophage Perforin-Like Immune Effector. Front Immunol 2020; 11:581906. [PMID: 33178209 PMCID: PMC7593815 DOI: 10.3389/fimmu.2020.581906] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 09/25/2020] [Indexed: 12/29/2022] Open
Abstract
Macrophage-expressed gene 1 [MPEG1/Perforin-2 (PRF2)] is an ancient metazoan protein belonging to the Membrane Attack Complex/Perforin (MACPF) branch of the MACPF/Cholesterol Dependent Cytolysin (CDC) superfamily of pore-forming proteins (PFPs). MACPF/CDC proteins are a large and extremely diverse superfamily that forms large transmembrane aqueous channels in target membranes. In humans, MACPFs have known roles in immunity and development. Like perforin (PRF) and the membrane attack complex (MAC), MPEG1 is also postulated to perform a role in immunity. Indeed, bioinformatic studies suggest that gene duplications of MPEG1 likely gave rise to PRF and MAC components. Studies reveal partial or complete loss of MPEG1 causes an increased susceptibility to microbial infection in both cells and animals. To this end, MPEG1 expression is upregulated in response to proinflammatory signals such as tumor necrosis factor α (TNFα) and lipopolysaccharides (LPS). Furthermore, germline mutations in MPEG1 have been identified in connection with recurrent pulmonary mycobacterial infections in humans. Structural studies on MPEG1 revealed that it can form oligomeric pre-pores and pores. Strikingly, the unusual domain arrangement within the MPEG1 architecture suggests a novel mechanism of pore formation that may have evolved to guard against unwanted lysis of the host cell. Collectively, the available data suggest that MPEG1 likely functions as an intracellular pore-forming immune effector. Herein, we review the current understanding of MPEG1 evolution, regulation, and function. Furthermore, recent structural studies of MPEG1 are discussed, including the proposed mechanisms of action for MPEG1 bactericidal activity. Lastly limitations, outstanding questions, and implications of MPEG1 models are explored in the context of the broader literature and in light of newly available structural data.
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Affiliation(s)
- Charles Bayly-Jones
- ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, VIC, Australia.,Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Siew Siew Pang
- ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, VIC, Australia.,Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - Bradley A Spicer
- ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, VIC, Australia.,Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
| | - James C Whisstock
- ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, VIC, Australia.,Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.,John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - Michelle A Dunstone
- ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Melbourne, VIC, Australia.,Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia
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8
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Schmitz-Abe K, Sanchez-Schmitz G, Doan RN, Hill RS, Chahrour MH, Mehta BK, Servattalab S, Ataman B, Lam ATN, Morrow EM, Greenberg ME, Yu TW, Walsh CA, Markianos K. Homozygous deletions implicate non-coding epigenetic marks in Autism spectrum disorder. Sci Rep 2020; 10:14045. [PMID: 32820185 PMCID: PMC7441318 DOI: 10.1038/s41598-020-70656-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 07/29/2020] [Indexed: 11/09/2022] Open
Abstract
More than 98% of the human genome is made up of non-coding DNA, but techniques to ascertain its contribution to human disease have lagged far behind our understanding of protein coding variations. Autism spectrum disorder (ASD) has been mostly associated with coding variations via de novo single nucleotide variants (SNVs), recessive/homozygous SNVs, or de novo copy number variants (CNVs); however, most ASD cases continue to lack a genetic diagnosis. We analyzed 187 consanguineous ASD families for biallelic CNVs. Recessive deletions were significantly enriched in affected individuals relative to their unaffected siblings (17% versus 4%, p < 0.001). Only a small subset of biallelic deletions were predicted to result in coding exon disruption. In contrast, biallelic deletions in individuals with ASD were enriched for overlap with regulatory regions, with 23/28 CNVs disrupting histone peaks in ENCODE (p < 0.009). Overlap with regulatory regions was further demonstrated by comparisons to the 127-epigenome dataset released by the Roadmap Epigenomics project, with enrichment for enhancers found in primary brain tissue and neuronal progenitor cells. Our results suggest a novel noncoding mechanism of ASD, describe a powerful method to identify important noncoding regions in the human genome, and emphasize the potential significance of gene activation and regulation in cognitive and social function.
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Affiliation(s)
- Klaus Schmitz-Abe
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA.,Divisions of Newborn Medicine and Manton Center for Orphan Disease Research, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.,Broad Institute of Harvard and MIT, Cambridge, MA, 02115, USA
| | - Guzman Sanchez-Schmitz
- Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.,Division of Infectious Diseases, Department of Pediatrics and Precision Vaccines Program, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Ryan N Doan
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - R Sean Hill
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Maria H Chahrour
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Bhaven K Mehta
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Sarah Servattalab
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Bulent Ataman
- Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA
| | - Anh-Thu N Lam
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA.,Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA
| | - Eric M Morrow
- Department of Molecular Biology, Cell Biology and Biochemistry and Department of Psychiatry and Human Behavior, Brown University, Providence, RI, 02912, USA
| | | | - Timothy W Yu
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA. .,Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
| | - Christopher A Walsh
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA. .,Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA. .,Broad Institute of Harvard and MIT, Cambridge, MA, 02115, USA. .,Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, 02115, USA. .,Department of Neurology, Harvard Medical School, Boston, MA, 02115, USA.
| | - Kyriacos Markianos
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, 02115, USA. .,Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA. .,Broad Institute of Harvard and MIT, Cambridge, MA, 02115, USA. .,Center for Data and Computational Sciences, Cooperative Studies Program, VA Boston Healthcare system, Boston, MA, 02130, USA.
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9
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He H, Li W, Shen B, Zhao H, Liu J, Qin J, Shi J, Yi X, Peng M, Huo R, Jin G. Gene expression changes induced by valproate in the process of rat hippocampal neural stem cells differentiation. Cell Biol Int 2019; 44:536-548. [PMID: 31642547 DOI: 10.1002/cbin.11254] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 10/19/2019] [Indexed: 12/14/2022]
Abstract
Valproate (VPA), an effective clinical approved anti-epileptic drug and mood stabilizer, has been believed to induce neuronal differentiation at the expense of inhibiting astrocytic and oligodendrocytic differentiation. Nevertheless, the involving mechanisms of it remain unclear yet. In the present study, we explored the global gene expression changes of fetus rat hippocampal neural stem cells following VPA treatment by high-throughput microarray. We obtained 874 significantly upregulated genes and 258 obviously downregulated genes (fold change > 2 and P < 0.05). Then, we performed gene ontology and pathway analyses of these differentially expressed genes and chose several genes associated with nervous system according to gene ontology analysis to conduct expression analysis to validate the reliability of the array results as well as reveal possible mechanisms of VPA. To get a better comprehension of the differentially regulated genes by VPA, we conducted protein-protein association analysis of these genes, which offered a source for further studies. In addition, we made the overlap between the VPA-downregulated genes and the predicted target genes of VPA-upregulated microRNAs (miRNAs), which were previously demonstrated. These overlapped genes may provide a source to find functional VPA/miRNA/mRNA axes during neuronal differentiation. This study first constructed a comprehensive potential downstream gene map of VPA in the process of neuronal differentiation.
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Affiliation(s)
- Hui He
- Department of Human Anatomy, Medical School, Nantong University, 19 Qixiu Road, Nantong, Chongchuan District, 226001, PR China
| | - Wen Li
- Department of Human Anatomy, Medical School, Nantong University, 19 Qixiu Road, Nantong, Chongchuan District, 226001, PR China
| | - Beilei Shen
- Department of Human Anatomy, Medical School, Nantong University, 19 Qixiu Road, Nantong, Chongchuan District, 226001, PR China
| | - Heyan Zhao
- Department of Human Anatomy, Medical School, Nantong University, 19 Qixiu Road, Nantong, Chongchuan District, 226001, PR China
| | - Juan Liu
- Department of Human Anatomy, Medical School, Nantong University, 19 Qixiu Road, Nantong, Chongchuan District, 226001, PR China
| | - Jianbing Qin
- Department of Human Anatomy, Medical School, Nantong University, 19 Qixiu Road, Nantong, Chongchuan District, 226001, PR China
| | - Jinhong Shi
- Department of Human Anatomy, Medical School, Nantong University, 19 Qixiu Road, Nantong, Chongchuan District, 226001, PR China
| | - Xin Yi
- Department of Human Anatomy, Medical School, Nantong University, 19 Qixiu Road, Nantong, Chongchuan District, 226001, PR China
| | - Min Peng
- Department of Human Anatomy, Medical School, Nantong University, 19 Qixiu Road, Nantong, Chongchuan District, 226001, PR China
| | - Ran Huo
- Department of Histology and Embryology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangning District, 211166, PR China
| | - Guohua Jin
- Department of Human Anatomy, Medical School, Nantong University, 19 Qixiu Road, Nantong, Chongchuan District, 226001, PR China
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10
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Ni T, Gilbert RJC. Repurposing a pore: highly conserved perforin-like proteins with alternative mechanisms. Philos Trans R Soc Lond B Biol Sci 2017; 372:20160212. [PMID: 28630152 PMCID: PMC5483515 DOI: 10.1098/rstb.2016.0212] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2017] [Indexed: 12/02/2022] Open
Abstract
Pore-forming proteins play critical roles in pathogenic attack and immunological defence. The membrane attack complex/perforin (MACPF) group of homologues represents, with cholesterol-dependent cytolysins, the largest family of such proteins. In this review, we begin by describing briefly the structure of MACPF proteins, outlining their common mechanism of pore formation. We subsequently discuss some examples of MACPF proteins likely implicated in pore formation or other membrane-remodelling processes. Finally, we focus on astrotactin and bone morphogenetic protein and retinoic acid-induced neural-specific proteins, highly conserved MACPF family members involved in developmental processes, which have not been well studied to date or observed to form a pore-and which data suggest may act by alternative mechanisms.This article is part of the themed issue 'Membrane pores: from structure and assembly, to medicine and technology'.
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Affiliation(s)
- Tao Ni
- Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Robert J C Gilbert
- Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
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11
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Berkowicz SR, Featherby TJ, Whisstock JC, Bird PI. Mice Lacking Brinp2 or Brinp3, or Both, Exhibit Behaviors Consistent with Neurodevelopmental Disorders. Front Behav Neurosci 2016; 10:196. [PMID: 27826231 PMCID: PMC5079073 DOI: 10.3389/fnbeh.2016.00196] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 09/29/2016] [Indexed: 12/31/2022] Open
Abstract
Background:Brinps 1–3, and Astrotactins (Astn) 1 and 2, are members of the Membrane Attack Complex/Perforin (MACPF) superfamily that are predominantly expressed in the mammalian brain during development. Genetic variation at the human BRINP2/ASTN1 and BRINP1/ASTN2 loci has been implicated in neurodevelopmental disorders. We, and others, have previously shown that Brinp1−/− mice exhibit behavior reminiscent of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Method: We created Brinp2−/− mice and Brinp3−/− mice via the Cre-mediated LoxP system to investigate the effect of gene deletion on anatomy and behavior. Additionally, Brinp2−/−Brinp3−/− double knock-out mice were generated by interbreeding Brinp2−/− and Brinp3−/− mice. Genomic validation was carried out for each knock-out line, followed by histological, weight and behavioral examination. Brinp1−/−Brinp2−/−Brinp3−/− triple knock-out mice were also generated by crossing Brinp2/3 double knock-out mice with previously generated Brinp1−/− mice, and examined by weight and histological analysis. Results:Brinp2−/− and Brinp3−/− mice differ in their behavior: Brinp2−/− mice are hyperactive, whereas Brinp3−/− mice exhibit marked changes in anxiety-response on the elevated plus maze. Brinp3−/− mice also show evidence of altered sociability. Both Brinp2−/− and Brinp3−/− mice have normal short-term memory, olfactory responses, pre-pulse inhibition, and motor learning. The double knock-out mice show behaviors of Brinp2−/− and Brinp3−/− mice, without evidence of new or exacerbated phenotypes. Conclusion:Brinp3 is important in moderation of anxiety, with potential relevance to anxiety disorders. Brinp2 dysfunction resulting in hyperactivity may be relevant to the association of ADHD with chromosome locus 1q25.2. Brinp2−/− and Brinp3−/− genes do not compensate in the mammalian brain and likely have distinct molecular or cell-type specific functions.
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Affiliation(s)
- Susan R Berkowicz
- Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University Clayton, VIC, Australia
| | - Travis J Featherby
- Melbourne Brain Centre, Florey Neuroscience Institute Parkville, VIC, Australia
| | - James C Whisstock
- Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash UniversityClayton, VIC, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, Monash UniversityClayton, VIC, Australia
| | - Phillip I Bird
- Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University Clayton, VIC, Australia
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12
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Berkowicz SR, Featherby TJ, Qu Z, Giousoh A, Borg NA, Heng JI, Whisstock JC, Bird PI. Brinp1(-/-) mice exhibit autism-like behaviour, altered memory, hyperactivity and increased parvalbumin-positive cortical interneuron density. Mol Autism 2016; 7:22. [PMID: 27042284 PMCID: PMC4818446 DOI: 10.1186/s13229-016-0079-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 02/11/2016] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND BMP/RA-inducible neural-specific protein 1 (Brinp1) is highly conserved in vertebrates, and continuously expressed in the neocortex, hippocampus, olfactory bulb and cerebellum from mid-embryonic development through to adulthood. METHODS Brinp1 knock-out (Brinp1(-/-)) mice were generated by Cre-recombinase-mediated removal of the third exon of Brinp1. Knock-out mice were characterised by behavioural phenotyping, immunohistochemistry and expression analysis of the developing and adult brain. RESULTS Absence of Brinp1 during development results in a behavioural phenotype resembling autism spectrum disorder (ASD), in which knock-out mice show reduced sociability and changes in vocalisation capacity. In addition, Brinp1(-/-) mice exhibit hyper-locomotor activity, have impaired short-term memory, and exhibit poor reproductive success. Brinp1(-/-) mice show increased density of parvalbumin-expressing interneurons in the adult mouse brain. Brinp1(-/-) mice do not show signs of altered neural precursor proliferation or increased apoptosis during late embryonic brain development. The expression of the related neuronal migration genes Astn1 and Astn2 is increased in the brains of Brinp1(-/-) mice, suggesting that they may ameliorate the effects of Brinp1 loss. CONCLUSIONS Brinp1 plays an important role in normal brain development and function by influencing neuronal distribution within the cortex. The increased cortical PV-positive interneuron density and altered behaviour of Brinp1(-/-) mice resemble features of a subset of human neurological disorders; namely autism spectrum disorder (ASD) and the hyperactivity aspect of attention deficit hyperactivity disorder (ADHD).
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Affiliation(s)
- Susan R. Berkowicz
- />Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800 Australia
| | - Travis J. Featherby
- />Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052 Australia
| | - Zhengdong Qu
- />Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800 Australia
| | - Aminah Giousoh
- />Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800 Australia
| | - Natalie A. Borg
- />Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800 Australia
| | - Julian I. Heng
- />Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800 Australia
| | - James C. Whisstock
- />Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800 Australia
- />Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800 Australia
| | - Phillip I. Bird
- />Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800 Australia
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13
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Chun HJE, Lim EL, Heravi-Moussavi A, Saberi S, Mungall KL, Bilenky M, Carles A, Tse K, Shlafman I, Zhu K, Qian JQ, Palmquist DL, He A, Long W, Goya R, Ng M, LeBlanc VG, Pleasance E, Thiessen N, Wong T, Chuah E, Zhao YJ, Schein JE, Gerhard DS, Taylor MD, Mungall AJ, Moore RA, Ma Y, Jones SJM, Perlman EJ, Hirst M, Marra MA. Genome-Wide Profiles of Extra-cranial Malignant Rhabdoid Tumors Reveal Heterogeneity and Dysregulated Developmental Pathways. Cancer Cell 2016; 29:394-406. [PMID: 26977886 PMCID: PMC5094835 DOI: 10.1016/j.ccell.2016.02.009] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 01/05/2016] [Accepted: 02/16/2016] [Indexed: 12/18/2022]
Abstract
Malignant rhabdoid tumors (MRTs) are rare lethal tumors of childhood that most commonly occur in the kidney and brain. MRTs are driven by SMARCB1 loss, but the molecular consequences of SMARCB1 loss in extra-cranial tumors have not been comprehensively described and genomic resources for analyses of extra-cranial MRT are limited. To provide such data, we used whole-genome sequencing, whole-genome bisulfite sequencing, whole transcriptome (RNA-seq) and microRNA sequencing (miRNA-seq), and histone modification profiling to characterize extra-cranial MRTs. Our analyses revealed gene expression and methylation subgroups and focused on dysregulated pathways, including those involved in neural crest development.
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Affiliation(s)
- Hye-Jung E Chun
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Emilia L Lim
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Alireza Heravi-Moussavi
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Saeed Saberi
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Karen L Mungall
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Mikhail Bilenky
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Annaick Carles
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Kane Tse
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Inna Shlafman
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Kelsey Zhu
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Jenny Q Qian
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Diana L Palmquist
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - An He
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - William Long
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Rodrigo Goya
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Michelle Ng
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Veronique G LeBlanc
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Erin Pleasance
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Nina Thiessen
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Tina Wong
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Eric Chuah
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Yong-Jun Zhao
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Jacquie E Schein
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Daniela S Gerhard
- Office of Cancer Genomics, National Cancer Institute, US National Institutes of Health, Bethesda, MD 20892, USA
| | - Michael D Taylor
- The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Andrew J Mungall
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Richard A Moore
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Yussanne Ma
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada
| | - Steven J M Jones
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada
| | - Elizabeth J Perlman
- Department of Pathology and Laboratory Medicine, Lurie Children's Hospital, Northwestern University's Feinberg School of Medicine and Robert H. Lurie Cancer Center, Chicago, IL 60611, USA
| | - Martin Hirst
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC V6T 1Z4, Canada
| | - Marco A Marra
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
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14
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Corradini BR, Iamashita P, Tampellini E, Farfel JM, Grinberg LT, Moreira-Filho CA. Complex network-driven view of genomic mechanisms underlying Parkinson's disease: analyses in dorsal motor vagal nucleus, locus coeruleus, and substantia nigra. BIOMED RESEARCH INTERNATIONAL 2014; 2014:543673. [PMID: 25525598 PMCID: PMC4261556 DOI: 10.1155/2014/543673] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 09/15/2014] [Indexed: 12/16/2022]
Abstract
Parkinson's disease (PD)—classically characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta—has a caudal-rostral progression, beginning in the dorsal motor vagal nucleus and, in a less extent, in the olfactory system, progressing to the midbrain and eventually to the basal forebrain and the neocortex. About 90% of the cases are idiopathic. To study the molecular mechanisms involved in idiopathic PD we conducted a comparative study of transcriptional interaction networks in the dorsal motor vagal nucleus (VA), locus coeruleus (LC), and substantia nigra (SN) of idiopathic PD in Braak stages 4-5 (PD) and disease-free controls (CT) using postmortem samples. Gene coexpression networks (GCNs) for each brain region (patients and controls) were obtained to identify highly connected relevant genes (hubs) and densely interconnected gene sets (modules). GCN analyses showed differences in topology and module composition between CT and PD networks for each anatomic region. In CT networks, VA, LC, and SN hub modules are predominantly associated with neuroprotection and homeostasis in the ageing brain, whereas in the patient's group, for the three brain regions, hub modules are mostly related to stress response and neuron survival/degeneration mechanisms.
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Affiliation(s)
- Beatriz Raposo Corradini
- Department of Pediatrics, Faculdade de Medicina da USP (FMUSP), Avenida Dr. Enéas Carvalho Aguiar 647, 5 Andar, 05403-900 São Paulo, SP, Brazil
| | - Priscila Iamashita
- Department of Pediatrics, Faculdade de Medicina da USP (FMUSP), Avenida Dr. Enéas Carvalho Aguiar 647, 5 Andar, 05403-900 São Paulo, SP, Brazil
| | - Edilaine Tampellini
- Brazilian Aging Brain Study Group (BEHEEC), LIM 22, FMUSP, 01246-903 São Paulo, SP, Brazil
- Hospital Israelita Albert Einstein, 05652-900 São Paulo, SP, Brazil
| | - José Marcelo Farfel
- Hospital Israelita Albert Einstein, 05652-900 São Paulo, SP, Brazil
- Division of Geriatrics, FMUSP, 01246-903 São Paulo, SP, Brazil
| | - Lea Tenenholz Grinberg
- Brazilian Aging Brain Study Group (BEHEEC), LIM 22, FMUSP, 01246-903 São Paulo, SP, Brazil
- Department of Pathology, FMUSP, 01246-903 São Paulo, SP, Brazil
- Department of Neurology and Pathology, University of California, San Francisco, CA 94143, USA
| | - Carlos Alberto Moreira-Filho
- Department of Pediatrics, Faculdade de Medicina da USP (FMUSP), Avenida Dr. Enéas Carvalho Aguiar 647, 5 Andar, 05403-900 São Paulo, SP, Brazil
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15
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Otsu M, Nakayama T, Inoue N. Pluripotent stem cell-derived neural stem cells: From basic research to applications. World J Stem Cells 2014; 6:651-657. [PMID: 25426263 PMCID: PMC4178266 DOI: 10.4252/wjsc.v6.i5.651] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 09/04/2014] [Accepted: 09/17/2014] [Indexed: 02/07/2023] Open
Abstract
Basic research on pluripotent stem cells is designed to enhance understanding of embryogenesis, whereas applied research is designed to develop novel therapies and prevent diseases. Attainment of these goals has been enhanced by the establishment of embryonic stem cell lines, the technological development of genomic reprogramming to generate induced-pluripotent stem cells, and improvements in vitro techniques to manipulate stem cells. This review summarizes the techniques required to generate neural cells from pluripotent stem cells. In particular, this review describes current research applications of a simple neural differentiation method, the neural stem sphere method, which we developed.
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16
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Chalei V, Sansom SN, Kong L, Lee S, Montiel JF, Vance KW, Ponting CP. The long non-coding RNA Dali is an epigenetic regulator of neural differentiation. eLife 2014; 3:e04530. [PMID: 25415054 PMCID: PMC4383022 DOI: 10.7554/elife.04530] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 11/21/2014] [Indexed: 12/11/2022] Open
Abstract
Many intergenic long noncoding RNA (lncRNA) loci regulate the expression of adjacent protein coding genes. Less clear is whether intergenic lncRNAs commonly regulate transcription by modulating chromatin at genomically distant loci. Here, we report both genomically local and distal RNA-dependent roles of Dali, a conserved central nervous system expressed intergenic lncRNA. Dali is transcribed downstream of the Pou3f3 transcription factor gene and its depletion disrupts the differentiation of neuroblastoma cells. Locally, Dali transcript regulates transcription of the Pou3f3 locus. Distally, it preferentially targets active promoters and regulates expression of neural differentiation genes, in part through physical association with the POU3F3 protein. Dali interacts with the DNMT1 DNA methyltransferase in mouse and human and regulates DNA methylation status of CpG island-associated promoters in trans. These results demonstrate, for the first time, that a single intergenic lncRNA controls the activity and methylation of genomically distal regulatory elements to modulate large-scale transcriptional programmes.
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Affiliation(s)
- Vladislava Chalei
- MRC Functional Genomics
Unit, Department of Physiology, Anatomy and Genetics,
University of Oxford, Oxford, United
Kingdom
| | - Stephen N Sansom
- MRC Functional Genomics
Unit, Department of Physiology, Anatomy and Genetics,
University of Oxford, Oxford, United
Kingdom
- Computational Genomics
Analysis and Training Programme, University of
Oxford, Oxford, United Kingdom
| | - Lesheng Kong
- MRC Functional Genomics
Unit, Department of Physiology, Anatomy and Genetics,
University of Oxford, Oxford, United
Kingdom
| | - Sheena Lee
- Department of
Physiology, Anatomy and Genetics, University of
Oxford, Oxford, United Kingdom
| | - Juan F Montiel
- MRC Functional Genomics
Unit, Department of Physiology, Anatomy and Genetics,
University of Oxford, Oxford, United
Kingdom
| | - Keith W Vance
- MRC Functional Genomics
Unit, Department of Physiology, Anatomy and Genetics,
University of Oxford, Oxford, United
Kingdom
| | - Chris P Ponting
- MRC Functional Genomics
Unit, Department of Physiology, Anatomy and Genetics,
University of Oxford, Oxford, United
Kingdom
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17
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Cloning and characterization of the porcine DBC1 gene encoding deleted in bladder cancer. Mol Biol Rep 2014; 42:383-91. [PMID: 25258124 DOI: 10.1007/s11033-014-3779-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 09/23/2014] [Indexed: 01/12/2023]
Abstract
Deleted in bladder cancer 1 (DBC1) is a tumour suppressor which is involved in the regulation of cell growth and programmed cell death. In this study we report the cloning and characterization of porcine DBC1 cDNA. RT-PCR cloning produced a cDNA with an open reading frame of 2,283 bp encoding a polypeptide of 761 amino acids with a predicted molecular mass of 88.6 kDa and estimated isoelectric point of 9.1. The encoded pig DBC1 protein shows a very high amino acid similarity to human (99 %) and to mouse (98 %) DBC1. The porcine DBC1 gene was mapped to chromosome 1. The nucleotide sequence of the promoter displayed a high degree of conservation of elements responsible for neuron-specific expression. The porcine DBC1 gene was found to be highly expressed in brain tissues. The methylation status of the porcine DBC1 gene was examined in brain and liver by bisulfite sequencing. Methylation percentages of 53-61 were observed for the gene body whereas significantly lower values (1-4 %) were found in exon 1 and the promoter sequence of DBC1. The sequences of the porcine DBC1 cDNA and the DBC1 promoter and exon 1 sequence have been submitted to DDBJ/EMBL/GenBank under the accession numbers KF733442 and KJ396193, respectively.
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18
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Cowley AW, Moreno C, Jacob HJ, Peterson CB, Stingo FC, Ahn KW, Liu P, Vannucci M, Laud PW, Reddy P, Lazar J, Evans L, Yang C, Kurth T, Liang M. Characterization of biological pathways associated with a 1.37 Mbp genomic region protective of hypertension in Dahl S rats. Physiol Genomics 2014; 46:398-410. [PMID: 24714719 DOI: 10.1152/physiolgenomics.00179.2013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The goal of the present study was to narrow a region of chromosome 13 to only several genes and then apply unbiased statistical approaches to identify molecular networks and biological pathways relevant to blood-pressure salt sensitivity in Dahl salt-sensitive (SS) rats. The analysis of 13 overlapping subcongenic strains identified a 1.37 Mbp region on chromosome 13 that influenced the mean arterial blood pressure by at least 25 mmHg in SS rats fed a high-salt diet. DNA sequencing and analysis filled genomic gaps and provided identification of five genes in this region, Rfwd2, Fam5b, Astn1, Pappa2, and Tnr. A cross-platform normalization of transcriptome data sets obtained from our previously published Affymetrix GeneChip dataset and newly acquired RNA-seq data from renal outer medullary tissue provided 90 observations for each gene. Two Bayesian methods were used to analyze the data: 1) a linear model analysis to assess 243 biological pathways for their likelihood to discriminate blood pressure levels across experimental groups and 2) a Bayesian graphical modeling of pathways to discover genes with potential relationships to the candidate genes in this region. As none of these five genes are known to be involved in hypertension, this unbiased approach has provided useful clues to be experimentally explored. Of these five genes, Rfwd2, the gene most strongly expressed in the renal outer medulla, was notably associated with pathways that can affect blood pressure via renal transcellular Na(+) and K(+) electrochemical gradients and tubular Na(+) transport, mitochondrial TCA cycle and cell energetics, and circadian rhythms.
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Affiliation(s)
- Allen W Cowley
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
| | - Carol Moreno
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Howard J Jacob
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Francesco C Stingo
- Department of Biostatistics, MD Anderson Cancer Center, Houston, Texas; and
| | - Kwang Woo Ahn
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Pengyuan Liu
- Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Purushottam W Laud
- Division of Biostatistics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Prajwal Reddy
- Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jozef Lazar
- Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Louise Evans
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Chun Yang
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Theresa Kurth
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Mingyu Liang
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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19
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Kobayashi M, Nakatani T, Koda T, Matsumoto KI, Ozaki R, Mochida N, Takao K, Miyakawa T, Matsuoka I. Absence of BRINP1 in mice causes increase of hippocampal neurogenesis and behavioral alterations relevant to human psychiatric disorders. Mol Brain 2014; 7:12. [PMID: 24528488 PMCID: PMC3928644 DOI: 10.1186/1756-6606-7-12] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Accepted: 02/03/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND We have previously identified BRINP (BMP/RA-inducible neural-specific protein-1, 2, 3) family genes that possess the ability to suppress cell cycle progression in neural stem cells. Of the three family members, BRINP1 is the most highly expressed in various brain regions, including the hippocampus, in adult mice and its expression in dentate gyrus (DG) is markedly induced by neural activity. In the present study, we generated BRINP1-deficient (KO) mice to clarify the physiological functions of BRINP1 in the nervous system. RESULTS Neurogenesis in the subgranular zone of dentate gyrus was increased in BRINP1-KO mice creating a more immature neuronal population in granule cell layer. The number of parvalbumin expressing interneuron in hippocampal CA1 subregion was also increased in BRINP1-KO mice. Furthermore, BRINP1-KO mice showed abnormal behaviors with increase in locomotor activity, reduced anxiety-like behavior, poor social interaction, and slight impairment of working memory, all of which resemble symptoms of human psychiatric disorders such as schizophrenia and attention-deficit/hyperactivity disorder (ADHD). CONCLUSIONS Absence of BRINP1 causes deregulation of neurogenesis and impairments of neuronal differentiation in adult hippocampal circuitry. Abnormal behaviors comparable to those of human psychiatric disorders such as hyperactivity and poor social behavior were observed in BRINP1-KO mice. These abnormal behaviors could be caused by alteration of hippocampal circuitry as a consequence of the lack of BRINP1.
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Affiliation(s)
- Miwako Kobayashi
- Laboratory of Physiological Chemistry, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan
| | - Toshiyuki Nakatani
- Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Nishi 6, Kita 12, Kita-ku, Sapporo 060-0812, Japan
| | - Toshiaki Koda
- Laboratory of Embryonic and Genetic Engineering, Graduate School of Life Science, Hokkaido University, Kita 21, Nishi 11, Kita-ku, Sapporo 001-0021, Japan
| | - Ken-ichi Matsumoto
- Department of Biosignaling and Radioisotope Experiment, Interdisciplinary Center for Science Research, Organization for Research, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Ryosuke Ozaki
- Laboratory of Physiological Chemistry, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan
| | - Natsuki Mochida
- Laboratory of Physiological Chemistry, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan
| | - Keizo Takao
- Section of Behavior Patterns, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, 38 Nishigo-naka Myodaiji, Okazaki 444-8585, Japan
- Japan Science and Technology Agency, CREST, Kawaguchi 332-0012, Japan
| | - Tsuyoshi Miyakawa
- Section of Behavior Patterns, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, 38 Nishigo-naka Myodaiji, Okazaki 444-8585, Japan
- Japan Science and Technology Agency, CREST, Kawaguchi 332-0012, Japan
- Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan
| | - Ichiro Matsuoka
- Laboratory of Physiological Chemistry, College of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan
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20
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Jeon SJ, Bak H, Seo J, Han SM, Lee SH, Han SH, Kwon KJ, Ryu JH, Cheong JH, Ko KH, Yang SI, Choi JW, Park SH, Shin CY. Oroxylin A Induces BDNF Expression on Cortical Neurons through Adenosine A2A Receptor Stimulation: A Possible Role in Neuroprotection. Biomol Ther (Seoul) 2013; 20:27-35. [PMID: 24116271 PMCID: PMC3792198 DOI: 10.4062/biomolther.2012.20.1.027] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Revised: 10/26/2011] [Accepted: 11/02/2011] [Indexed: 11/05/2022] Open
Abstract
Oroxylin A is a flavone isolated from a medicinal herb reported to be effective in reducing the inflammatory and oxidative stresses. It also modulates the production of brain derived neurotrophic factor (BDNF) in cortical neurons by the transactivation of cAMP response element-binding protein (CREB). As a neurotrophin, BDNF plays roles in neuronal development, differentiation, synaptogenesis, and neural protection from the harmful stimuli. Adenosine A2A receptor colocalized with BDNF in brain and the functional interaction between A2A receptor stimulation and BDNF action has been suggested. In this study, we investigated the possibility that oroxylin A modulates BDNF production in cortical neuron through the regulation of A2A receptor system. As ex-pected, CGS21680 (A2A receptor agonist) induced BDNF expression and release, however, an antagonist, ZM241385, prevented oroxylin A-induced increase in BDNF production. Oroxylin A activated the PI3K-Akt-GSK-3β signaling pathway, which is inhibited by ZM241385 and the blockade of the signaling pathway abolished the increase in BDNF production. The physiological roles of oroxylin A-induced BDNF production were demonstrated by the increased neurite extension as well as synapse formation from neurons. Overall, oroxylin A might regulate BDNF production in cortical neuron through A2A receptor stimulation, which promotes cellular survival, synapse formation and neurite extension.
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Affiliation(s)
- Se Jin Jeon
- Department of Pharmacology, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742 ; Neuroscience Research Center, Institute for Advanced Biomedical Sciences
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