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

  • Adv Sci (Weinh). 2025 Aug;12(30):e00461. doi: 10.1002/advs.202500461.
Ming Yuan  1  2  3 ,  Shaopeng Chen  1  2  3 ,  Zhensen Lin  1  2  3 ,  Runfeng Yu  1  2  3 ,  Kang Chao  2  3  4 ,  Shubiao Ye  1  2  3 ,  Qing Li  2  3  4 ,  Haoxian Ke  5 ,  Chi Zhang  1  2  3 ,  Junfeng Huang  5 ,  Guanzhan Liang  1  2  3 ,  Tuo Hu  1  2  3 ,  Xiang Gao  2  3  4 ,  Ping Lan  1  2  3  6 ,  Xianrui Wu  5
Affiliations
  • 1. Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China.
  • 2. Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China.
  • 3. Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China.
  • 4. Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China.
  • 5. Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510288, China.
  • 6. State Key Laboratory of Oncology in South China, Guangzhou, Guangdong, 510288, China.
PMID: 40650658 DOI: 10.1002/advs.202500461
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.

Keywords
ACSS2; histone lysine crotonylation; inflammatory bowel disease; intestinal barrier.
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