Sin3a_Online_Materials_03062020-Gu.docx (43.55 MB)

Coregulator Sin3a promotes postnatal murine β-cell fitness by regulating genes in Ca2+ homeostasis, cell survival, vesicle biosynthesis, glucose metabolism, and stress response

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posted on 03.04.2020 by Ada Admin, Xiaodun Yang, Sarah M. Graff, Cody N. Heiser, Kung-Hsien Ho, Bob Chen, Alan J. Simmons, Austin N. Southard-Smith, Gregory David, David A. Jacobson, Irina Kaverina, Christopher V. E. Wright, Ken S. Lau, Guoqiang Gu
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 co-produced 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-seq 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. Lastly, 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.

Funding

This study is supported by grants from NIDDK (DK065949 for GG, DK101988 for IK and GG, and DK103831 and CA095103 for K.S.L) and JDRF (1-2009-371 for GG). Confocal and TEM imaging was performed with Vanderbilt University Cell Imaging Shared Resource (supported by NIH grants CA68485, DK20593, 500 DK58404, DK59637 and EY08126).

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