Class IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation

• 成果类型: Article
• 署名作者: Cheung, Ka Lung; Zhao, Li; Sharma, Rajal; Ghosh, Anurupa Abhijit; Appiah, Michael; Sun, Yifei; Jaganathan, Anbalagan; Hu, Yuan; Lejeune, Alannah; Xu, Feihong; Han, Xinye; Wang, Xueting; Zhang, Fan; Ren, Chunyan; Walsh, Martin J.; Xiong, Huabao; Tsankov, Alexander; Zhou, Ming-Ming
• 署名单位: Icahn School of Medicine at Mount Sinai; Jilin University; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12116
• DOI: 10.1073/pnas.2312111121
• 发表日期: 2024-04-30
• 关键词: histone deacetylase inhibitors; ror-gamma-t; t(h)17 differentiation; suppresses; expression; effector; distinct; lineage; disease; inflammation

摘要

Class II histone deacetylases (HDACs) are important in regulation of gene transcription during T cell development. However, our understanding of their cell - specific functions is limited. In this study, we reveal that class IIa Hdac4 and Hdac7 (Hdac4/7) are selectively induced in transcription, guiding the lineage - specific differentiation of mouse T - helper 17 (Th17) cells from naive CD4 + T cells. Importantly, Hdac4/7 are functionally dispensable in other Th subtypes. Mechanistically, Hdac4 interacts with the transcription factor (TF) JunB, facilitating the transcriptional activation of Th17 signature genes such as Il17a/f . Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1 - Hdac3 corepressors to repress transcription of Th17 negative regulators, including Il2 , in Th17 cell differentiation. Inhibiting Hdac4/7 through pharmacological or genetic methods effectively mitigates Th17 cell-mediated intestinal inflammation in a colitis mouse model. Our study uncovers molecular mechanisms where HDAC4 and HDAC7 function distinctively yet cooperatively in regulating ordered gene transcription during Th17 cell differentiation. These findings suggest a potential therapeutic strategy of targeting HDAC4/7 for treating Th17 - related inflammatory diseases, such as ulcerative colitis.