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 2020-04-03, 22:53 authored by Ada AdminAda 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 GuSwi-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.