HAT1 Regulates Intestinal Stem Cell Proliferation and Differentiation [CUT&Tag]

ABSTRACT: Stem cells are critical for the development and maintenance of tissue integrity. An important example is intestinal stem cells (ISCs) that generate all cell types necessary for formation of the intestine. HAT1, a histone acetyltransferase that acetylates newly synthesized histone H4 molecules on lysine residues 5 and 12 during replication-coupled chromatin assembly, is specifically expressed in intestinal stem and progenitor cells located in intestinal crypts. To determine if HAT1 is important for intestinal stem and progenitor cell function, we generated an inducible deletion of the HAT1 gene in intestinal epithelial cells. Loss of HAT1 resulted in morphological defects in the proximal small intestine. 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 intestinal stem cell differentiation, including an increase in the number of Goblet cells and the mislocalization of Paneth cells. HAT1 is specifically responsible for the acetylation of histone H4 lysine 5 (H4K5ac) in intestinal stem cells. Genome-wide characterization of HAT1-dependent H4K5ac in intestinal crypt cells indicates that the most significant loss of H4K5ac occurs in lamina-associated domains (LADs). Loss of H4K5ac in LADs is accompanied by an increase in histone H3 K9 tri-methylation indicating that HAT1 regulates LAD chromatin structure in intestinal crypt cells. A direct role for HAT1 in intestinal stem cell function was demonstrated using organoids in culture. HAT1 is required for the differentiation of organoids and for the maintenance of Lgr5+ cells stem cells. These results indicate that HAT1 is required for the proper regulation of intestinal stem cell growth and differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE319094 | GEO | 2026/09/02

REPOSITORIES: GEO