Coregulator Sin3a Promotes Postnatal Murine β-Cell Fitness by Regulating Genes in Ca 2+ Homeostasis, Cell Survival, Vesicle Biosynthesis, Glucose Metabolism, and Stress Response

Diabetes. 2020 Jun;69(6):1219-1231. doi: 10.2337/db19-0721. Epub 2020 Apr 3.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Calcium / metabolism*
  • Cell Survival
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism*
  • Female
  • Gene Expression Regulation, Developmental
  • Homeostasis
  • Insulin-Secreting Cells / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Sin3 Histone Deacetylase and Corepressor Complex / genetics
  • Sin3 Histone Deacetylase and Corepressor Complex / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse
  • Repressor Proteins
  • SIN3A transcription factor
  • Sin3b protein, mouse
  • Sin3 Histone Deacetylase and Corepressor Complex
  • Calcium