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

作者：Ka Lung Cheung, Li Zhao, Rajal Sharma, Anurupa Ghosh, Michael G. Appiah, Yifei Sun, Anbalagan Jaganathan, Yuan Hu, Alannah Lejeune, Feihong Xu, Xinye Han, Xueting Wang, Fan Zhang, Chunyan Ren, Martin J. Walsh, Huabao Xiong, Alexander M. Tsankov, Ming‐Ming Zhou · 发表于：Proceedings of the National Academy of Sciences · 年份：2024 · DOI：10.1073/pnas.2312111121 · 被引用次数：20 · 研究领域：Histone Deacetylase Inhibitors Research、Immune Cell Function and Interaction、Psoriasis: Treatment and Pathogenesis

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.