Coregulator Sin3a Promotes Postnatal Murine β-Cell Fitness by Regulating Genes in Ca2+ Homeostasis, Cell Survival, Vesicle Biosynthesis, Glucose Metabolism, and Stress Response
- 3 April 2020
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 69 (6), 1219-1231
- https://doi.org/10.2337/db19-0721
Abstract
Swi-independent 3a and 3b (Sin3a and Sin3b) are paralogous transcriptional coregulators that direct cellular differentiation, survival, and function. Here, we report that mouse Sin3a and Sin3b are coproduced in most pancreatic cells during embryogenesis but become much more enriched in endocrine cells in adults, implying continued essential roles in mature endocrine cell function. Mice with loss of Sin3a in endocrine progenitors were normal during early postnatal stages but gradually developed diabetes before weaning. These physiological defects were preceded by the compromised survival, insulin-vesicle packaging, insulin secretion, and nutrient-induced Ca2+ influx of Sin3a-deficient β-cells. RNA sequencing coupled with candidate chromatin immunoprecipitation assays revealed several genes that could be directly regulated by Sin3a in β-cells, which modulate Ca2+/ion transport, cell survival, vesicle/membrane trafficking, glucose metabolism, and stress responses. Finally, mice with loss of both Sin3a and Sin3b in multipotent embryonic pancreatic progenitors had significantly reduced islet cell mass at birth, caused by decreased endocrine progenitor production and increased β-cell death. These findings highlight the stage-specific requirements for the presumed “general” coregulators Sin3a and Sin3b in islet β-cells, with Sin3a being dispensable for differentiation but required for postnatal function and survival.Keywords
Funding Information
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-106228, DK-103831, CA-095103, DK-065949, DK-20593)
This publication has 51 references indexed in Scilit:
- ING1 induces apoptosis through direct effects at the mitochondriaCell Death & Disease, 2013
- The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasisNature, 2011
- MafA and MafB activity in pancreatic β cellsTrends in Endocrinology & Metabolism, 2011
- TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelityNature, 2011
- Calcium-activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue induced electrical responsesJournal Of Physiology-London, 2010
- Characterization of Erg K+ Channels in α- and β-Cells of Mouse and Human IsletsOnline Journal of Public Health Informatics, 2009
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- Specific requirement of the chromatin modifier mSin3B in cell cycle exit and cellular differentiationProceedings of the National Academy of Sciences of the United States of America, 2008
- Urocortin 3 regulates glucose-stimulated insulin secretion and energy homeostasisProceedings of the National Academy of Sciences of the United States of America, 2007
- Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profilesProceedings of the National Academy of Sciences of the United States of America, 2005