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 decre...
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Wiley
2025-08-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202500461 |
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| author | Ming Yuan Shaopeng Chen Zhensen Lin Runfeng Yu Kang Chao Shubiao Ye Qing Li Haoxian Ke Chi Zhang Junfeng Huang Guanzhan Liang Tuo Hu Xiang Gao Ping Lan Xianrui Wu |
| author_facet | Ming Yuan Shaopeng Chen Zhensen Lin Runfeng Yu Kang Chao Shubiao Ye Qing Li Haoxian Ke Chi Zhang Junfeng Huang Guanzhan Liang Tuo Hu Xiang Gao Ping Lan Xianrui Wu |
| author_sort | Ming Yuan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d6f7cbf88aed437e9e886963d9376a1a |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-d6f7cbf88aed437e9e886963d9376a1a2025-08-20T11:56:11ZengWileyAdvanced Science2198-38442025-08-011230n/an/a10.1002/advs.202500461ACSS2‐Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7Ming Yuan0Shaopeng Chen1Zhensen Lin2Runfeng Yu3Kang Chao4Shubiao Ye5Qing Li6Haoxian Ke7Chi Zhang8Junfeng Huang9Guanzhan Liang10Tuo Hu11Xiang Gao12Ping Lan13Xianrui Wu14Department of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaGuangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaGuangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaDepartment of Gastrointestinal Surgery Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou Guangdong 510288 ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaDepartment of Gastrointestinal Surgery Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou Guangdong 510288 ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaGuangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaDepartment of General Surgery (Colorectal Surgery) The Sixth Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510655 ChinaDepartment of Gastrointestinal Surgery Sun Yat‐sen Memorial Hospital Sun Yat‐sen University Guangzhou Guangdong 510288 ChinaAbstract 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.https://doi.org/10.1002/advs.202500461ACSS2inflammatory bowel diseaseintestinal barrierhistone lysine crotonylation |
| spellingShingle | Ming Yuan Shaopeng Chen Zhensen Lin Runfeng Yu Kang Chao Shubiao Ye Qing Li Haoxian Ke Chi Zhang Junfeng Huang Guanzhan Liang Tuo Hu Xiang Gao Ping Lan Xianrui Wu ACSS2‐Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7 Advanced Science ACSS2 inflammatory bowel disease intestinal barrier histone lysine crotonylation |
| title | ACSS2‐Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7 |
| title_full | ACSS2‐Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7 |
| title_fullStr | ACSS2‐Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7 |
| title_full_unstemmed | ACSS2‐Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7 |
| title_short | ACSS2‐Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7 |
| title_sort | acss2 mediated histone h4 lysine 12 crotonylation h4k12cr alleviates colitis via enhancing transcription of cldn7 |
| topic | ACSS2 inflammatory bowel disease intestinal barrier histone lysine crotonylation |
| url | https://doi.org/10.1002/advs.202500461 |
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