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Tytuł:
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SMNDC1 links chromatin remodeling and splicing to regulate pancreatic hormone expression.
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Autorzy:
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Casteels T; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
Bajew S; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Carrer del Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, Carrer del Dr. Aiguader 88, 08003 Barcelona, Spain.
Reiniš J; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
Enders L; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
Schuster M; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
Fontaine F; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
Müller AC; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
Wagner BK; Broad Institute, 415 Main Street, Cambridge, MA 02142, USA.
Bock C; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria; Medical University of Vienna, Center for Medical Statistics, Informatics, and Intelligent Systems, Institute of Artificial Intelligence, 1090 Vienna, Austria.
Kubicek S; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria. Electronic address: .
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Źródło:
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Cell reports [Cell Rep] 2022 Aug 30; Vol. 40 (9), pp. 111288.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: [Cambridge, MA] : Cell Press, c 2012-
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MeSH Terms:
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Chromatin Assembly and Disassembly*
Glucagon-Secreting Cells*/metabolism
Insulin-Secreting Cells*/metabolism
Islets of Langerhans*/metabolism
RNA Splicing*/genetics
RNA Splicing Factors*/metabolism
SMN Complex Proteins*/metabolism
Animals ; Humans ; Insulin/metabolism ; Insulin Secretion ; Mice ; Transcription Factors/metabolism
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Contributed Indexing:
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Keywords: CP: Metabolism; CP: Molecular biology; RNAi screen; SMNDC1; alpha cells; beta cells; chromatin remodelers; insulin transcription; pancreatic islets; splicing
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Substance Nomenclature:
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0 (Insulin)
0 (RNA Splicing Factors)
0 (SMN Complex Proteins)
0 (SMNDC1 protein, human)
0 (Transcription Factors)
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Entry Date(s):
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Date Created: 20220831 Date Completed: 20220908 Latest Revision: 20230809
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Update Code:
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20240105
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DOI:
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10.1016/j.celrep.2022.111288
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PMID:
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36044849
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Insulin expression is primarily restricted to the pancreatic β cells, which are physically or functionally depleted in diabetes. Identifying targetable pathways repressing insulin in non-β cells, particularly in the developmentally related glucagon-secreting α cells, is an important aim of regenerative medicine. Here, we perform an RNA interference screen in a murine α cell line to identify silencers of insulin expression. We discover that knockdown of the splicing factor Smndc1 triggers a global repression of α cell gene-expression programs in favor of increased β cell markers. Mechanistically, Smndc1 knockdown upregulates the β cell transcription factor Pdx1 by modulating the activities of the BAF and Atrx chromatin remodeling complexes. SMNDC1's repressive role is conserved in human pancreatic islets, its loss triggering enhanced insulin secretion and PDX1 expression. Our study identifies Smndc1 as a key factor connecting splicing and chromatin remodeling to the control of insulin expression in human and mouse islet cells.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)