Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling

Cemre Celen, Jen Chieh Chuang, Shunli Shen, Lin Li, Gianna Maggiore, Yuemeng Jia, Xin Luo, Austin Moore, Yunguan Wang, Jordan E. Otto, Clayton K. Collings, Zixi Wang, Xuxu Sun, Ibrahim Nassour, Jiyoung Park, Alexandra Ghaben, Tao Wang, Sam C Wang, Philipp E. Scherer, Cigall KadochHao Zhu

Research output: Contribution to journalArticlepeer-review

Abstract

The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here, we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration. Arid1a is highly expressed in quiescent β-cells but is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice are protected against streptozotocin-induced diabetes. Cell-type and temporally specific genetic dissection show that β-cell-specific Arid1a deletion can potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets reveal increased neuregulin-ERBB-NR4A signaling. Chemical inhibition of ERBB or NR4A1 blocks increased regeneration associated with Arid1a loss. Mammalian SWI/SNF (mSWI/SNF) complex activity is a barrier to β-cell regeneration in physiologic and disease states.

Original languageEnglish (US)
Article number111581
JournalCell Reports
Volume41
Issue number5
DOIs
StatePublished - Nov 1 2022

Keywords

  • Arid1a
  • chromatin remodeling
  • CP: Cell biology
  • CP: Developmental biology
  • diabetes
  • EGFR/ERBB
  • islets
  • NR4A nuclear receptors
  • NRG/EGF signaling
  • SWI/SNF
  • β-cell regeneration

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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