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

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 was able to block increased regeneration associated with Arid1a loss. mSWI/SNF complex activity is a barrier to β-cell regeneration in physiologic and disease states. ChIP-Seq of the histone modification H3K27ac in MIN6 cells for wildtype, heterozygous ARID1A KO, and homozygous ARID1A KO samples.