biostudies-literatureCheung KLNIAID NIH HHSColitis-Crohn ForeningenHHS | NIH | NIAID | Division of Intramural ResearchNIH HHSe2312111121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11067014biostudies-literatureUnknown121(18)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 <i>Il17a/f</i>. Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators, including <i>Il2</i>, 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.Proceedings of the National Academy of Sciences of the United States of AmericaClass IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation.PMC11067014R01AI124465579304S10 OD030463S10 OD026880R01 AI124465R01 AI168004R01AI168004Zhang FTsankov AHu YSharma RAppiah MHan XXu FLeJeune ASun YRen CCheung KLZhao LGhosh AAWalsh MJJaganathan AZhou MMWang XXiong HfalseClass IIa HDAC4 and HDAC7 cooperatively regulate gene transcription in Th17 cell differentiation.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 <i>Il17a/f</i>. Conversely, Hdac7 collaborates with the TF Aiolos and Smrt/Ncor1-Hdac3 corepressors to repress transcription of Th17 negative regulators, including <i>Il2</i>, 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.2024-01-01T00:00:00Z2024 Apr2025-04-04T02:20:52.007Z2025-04-04T02:20:52.007ZS-EPMC110670143865704110.1073/pnas.2312111121