Prmt5 is essential for intestinal stem cell maintenance and homeostasis.

Intestinal homeostasis relies on the continuous renewal of intestinal stem cells (ISCs), which could be epigenetically regulated. While protein arginine methyltransferase 5 (Prmt5) is known to play a key role in multiple organs as an epigenetic modifier, its specific function in maintaining intestinal homeostasis remains to be elucidated. Here, we show that Prmt5 is highly expressed in mouse crypts. The deletion of Prmt5 results in ISCs deficiency, ectopic localization of Paneth cells, and spontaneous colitis. Mechanistically, Prmt5 sustains a high level of H3K27ac accumulation by inhibiting Hdac9 expression in the intestinal epithelium, and maintains the stemness of ISCs in a cell-autonomous manner. Notably, inhibition of histone deacetylases can rescue both self-renewal and differentiation capacities of Prmt5-depleted ISCs. These findings highlight Prmt5 as a critical regulator in intestinal epithelium development and tissue homeostasis.