Histone acetyltransferase HAT1 regulates intestinal stem cell proliferation and differentiation

Stem cells are critical for the development and maintenance of tissue integrity. An important example is intestinal stem cells (ISCs) that generate all epithelial cell types necessary for formation of the intestinal lining. HAT1 is a histone acetyltransferase that acetylates newly synthesized histone H4 molecules on lysine residues 5 and 12 during replication-coupled chromatin assembly. Within the intestine, HAT1 is specifically expressed in intestinal stem and progenitor cells. We generated an inducible deletion of the Hat1 gene in intestinal epithelial cells. Following loss of Hat1, intestinal crypts became elongated, with an increase in stem and progenitor cell proliferation and an increase in the population of OLFM+ cells. Loss of Hat1 also resulted in alterations in ISC differentiation, including an increase in the number of Goblet cells and the mislocalization of Paneth cells into villi. HAT1 is specifically responsible for the acetylation of histone H4 lysine 5 (H4K5ac) in ISCs. Genome-wide characterization of HAT1-dependent H4K5ac in intestinal crypt cells indicates that the most significant loss of H4K5ac occurs regions of the genome that correspond to in lamina-associated domains, as defined in mouse embryonic fibroblasts. Loss of H4K5ac is accompanied by an increase in histone H3 K9 tri-methylation, indicating that HAT1 regulates genome-wide histone modification patterns in intestinal crypt cells. A direct role for HAT1 in ISC function was demonstrated using organoids in culture. HAT1 is required for differentiation in organoids and for the maintenance of Lgr5+ stem cells. These results indicate that HAT1 is required for the proper regulation of ISC renewal and differentiation.