ARID1A is required for proper identity and potential of colon stem cells

Loss of function mutations in the SWI/SNF chromatin remodeling complex subunit ARID1A commonly occur in colorectal cancer and inflammatory bowel diseases, pointing to an important homeostatic role in the large intestine. However, we know little about the chromatin basis for ARID1A function in intestinal stem cells. Here, we characterize the developmental role of ARID1A in colon stem cell maintenance and model the impact of ARID1A loss of function using CRISPR-Cas9 edited human colon organoids (hCOs). We show that ARID1A-BAF maintains continuous access to tens of thousands of enhancer elements in colon stem cells and plays a dynamic role during differentiation, serving to both augment existing enhancers and establish de novo accessibilities. ARID1A loss decommissions active enhancers and incurs widespread transcriptional changes affecting stem cell identity, including upregulation of ASCL2, EPHB3, TERT, and MYC and marked by increased colony forming capacity. In differentiating conditions, ARID1A deficient organoids could not effectively produce mature cell types, particularly goblet cells and colonocytes. Mechanistically, we show that ARID1A-based chromatin remodeling is required for the regulatory actions of transcription factors such as HNF4A, ELF3 and, most potently, the master intestinal regulator CDX2. Our results reveal the molecular framework for ARID1A-BAF chromatin functions in colon stem cells and provide developmental context to its recurrent alteration in digestive diseases.