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

Abstract

The dynamic regulation of {beta}-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 {beta}-cell regeneration. Arid1a is highly expressed in quiescent {beta}-cells but is physiologically suppressed when {beta}-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice were protected against streptozotocin induced diabetes. Cell-type and temporally specific genetic dissection showed that {beta}-cell specific Arid1a deletion could potentiate {beta}-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets revealed increased Neuregulin-ERBB-NR4A signaling. Functionally, ERBB3 overexpression in {beta}-cells was sufficient to protect against diabetes, and chemical inhibition of ERBB or NR4A was able to block increased regeneration associated with Arid1a loss. mSWI/SNF complex activity is a barrier to {beta}-cell regeneration in physiologic and disease states.