ACSS2‐Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7

Abstract Histone lysine crotonylation (Kcr), a highly conserved posttranslational modification, plays critical roles in various biological processes. Nevertheless, the dynamic alterations and functions of histone Kcr in inflammatory bowel disease (IBD) remain poorly explored. Herein, a notable decrease of both Pan‐Kcr and ACSS2 (acyl‐CoA synthetase short‐chain family member 2), the key enzyme for crotonyl‐CoA generation, is revealed in inflamed intestinal epithelial cells. Genetic or pharmacological inhibition of ACSS2 dramatically impairs mouse intestinal barrier integrity and exacerbates colitis. Mechanistically, ACSS2‐mediated histone H4 lysine 12 crotonylation (H4K12cr) upregulates CLDN7 expression to fortify intestinal epithelial barrier, which can be augmented by crotonate supplementation. Furthermore, tumor necrosis factor‐α (TNF‐α) is revealed to enhance the m6A modification of ACSS2 mRNA, consequently destabilizing and downregulating ACSS2 . Combinational therapy involving anti‐TNF‐α and crotonate can significantly ameliorate colitis. Overall, ACSS2‐mediated H4K12cr emerges as a pivotal modulator governing intestinal barrier function during IBD progression.