SMNDC1 links chromatin remodeling and splicing to regulate pancreatic hormone expression
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- dc.contributor.author Casteels, Tamara
- dc.contributor.author Bajew, Simon, 1994-
- dc.contributor.author Reiniš, Jiří
- dc.contributor.author Enders, Lennart
- dc.contributor.author Schuster, Michael
- dc.contributor.author Fontaine, Frédéric
- dc.contributor.author Müller, André C.
- dc.contributor.author Wagner, Bridget K.
- dc.contributor.author Bock, Christoph
- dc.contributor.author Kubicek, Stefan
- dc.date.accessioned 2022-10-26T06:25:32Z
- dc.date.available 2022-10-26T06:25:32Z
- dc.date.issued 2022
- dc.description.abstract 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.
- dc.description.sponsorship This work was supported by JDRF grants 3-SRA-2015-20-Q-R and 17-2011-258. Research in the Kubicek lab is supported by the Austrian Federal Ministry for Digital and Economic Affairs and the National Foundation for Research, Technology, and Development; the Austrian Science Fund (FWF) F4701; and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (ERC-CoG-772437).
- dc.format.mimetype application/pdf
- dc.identifier.citation Casteels T, Bajew S, Reiniš J, Enders L, Schuster M, Fontaine F, Müller AC, Wagner BK, Bock C, Kubicek S. SMNDC1 links chromatin remodeling and splicing to regulate pancreatic hormone expression. Cell Rep. 2022 Aug 30;40(9):111288. DOI: 10.1016/j.celrep.2022.111288
- dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2022.111288
- dc.identifier.issn 2211-1247
- dc.identifier.uri http://hdl.handle.net/10230/54590
- dc.language.iso eng
- dc.publisher Elsevier
- dc.relation.ispartof Cell Rep. 2022 Aug 30;40(9):111288
- dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/772437
- dc.rights © 2022 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
- dc.subject.keyword CP: Metabolism
- dc.subject.keyword CP: Molecular biology
- dc.subject.keyword RNAi screen
- dc.subject.keyword SMNDC1
- dc.subject.keyword Alpha cells
- dc.subject.keyword Beta cells
- dc.subject.keyword Chromatin remodelers
- dc.subject.keyword Insulin transcription
- dc.subject.keyword Pancreatic islets
- dc.subject.keyword Splicing
- dc.title SMNDC1 links chromatin remodeling and splicing to regulate pancreatic hormone expression
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion