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Coregulator Sin3a Promotes Postnatal Murine ß-Cell Fitness by Regulating Genes
in Ca2+ Homeostasis, Cell Survival, Vesicle Biosynthesis, Glucose Metabolism,
and Stress Response.
Authors Yang X, Graff SM, Heiser CN, Ho KH, Chen B, Simmons AJ, Southard-Smith AN, David
G, Jacobson DA, Kaverina I, Wright CVE, Lau KS, Gu G
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal Diabetes
Year 2020
Date Published 6/1/2020
Volume : Pages 69 : 1219 - 1231
PubMed Reference 32245798
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 ß-cells. RNA
sequencing coupled with candidate chromatin immunoprecipitation assays revealed
several genes that could be directly regulated by Sin3a in ß-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 ß-cell death. These findings highlight the
stage-specific requirements for the presumed "general" coregulators Sin3a and
Sin3b in islet ß-cells, with Sin3a being dispensable for differentiation but
required for postnatal function and survival.


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