ARID3A coordinates the proliferation-differentiation switch of transit-amplifying cells in the intestine

Abstract

SummaryIntestinal stem cells (ISCs) at the crypt base divide and give rise to progenitor cells that have the capacity to proliferate and differentiate into various mature epithelial cell types in the transit-amplifying (TA) zone. Here, we identified the transcription factor ARID3A as a novel regulator of intestinal epithelial cell proliferation and differentiation at the TA compartment. We show that ARID3A forms an expression gradient from villus tip to the early progenitors at the crypts mediated by TGF-β and WNT signalling. Intestinal epithelial-specific deletion ofArid3areduces proliferation of TA cells. Bulk and single cell transcriptomic analysis shows increased enterocyte differentiation and reduced secretory cells in theArid3acKO intestine. Interestingly, upper-villus gene signatures of both enterocytes and secretory cells are enriched in the mutant intestine. We find that the enhanced enterocyte differentiation in theArid3acKO intestine is caused by increased binding of HNF1 and HNF4. Finally, we show that loss ofArid3aimpairs irradiation-induced regenerative process by altering the dynamics of proliferation and apoptosis. Our findings imply that ARID3A may play a gatekeeping role in the TA compartment to maintain the “just-right” proliferation-to-differentiation ratio for tissue homeostasis and plasticity.