Details

Autor(en) / Beteiligte

• Casteels, Tamara
• Bajew, Simon
• Reiniš, Jiří
• Enders, Lennart
• Schuster, Michael
• Fontaine, Frédéric
• Müller, André C.
• Wagner, Bridget K.
• Bock, Christoph
• Kubicek, Stefan

Titel

SMNDC1 links chromatin remodeling and splicing to regulate pancreatic hormone expression

Ist Teil von

• Cell reports (Cambridge), 2022-08, Vol.40 (9), p.111288-111288, Article 111288

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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. [Display omitted] •Smndc1 represses insulin transcription and PDX1 mRNA stability in α cells•Smndc1 regulates splicing and expression of the chromatin remodeler Atrx•Smndc1 maintains deposition of repressive H3K9me3 marks at disallowed genes•Loss of SMNDC1 in pancreatic human islets improves their glucose responsiveness Casteels et al. show that the splicing factor Smndc1 is important in the maintenance of pancreatic α cell identity and functionality. Its loss in α cells triggers an increase in β cell markers, chromatin accessibility, insulin transcription, and stabilization of the key β cell transcription factor Pdx1.