PDF(Pubmed)
Abstract：
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.
摘要：
II类组蛋白脱乙酰酶（HDAC）在T细胞发育过程中对基因转录的调节很重要。然而,我们对其细胞特异性功能的理解是有限的。在这项研究中,我们发现IIa类Hdac4和Hdac7（Hdac4/7）在转录中被选择性诱导，指导小鼠T辅助细胞17（Th17）细胞从幼稚CD4T细胞的谱系特异性分化。重要的是,Hdac4/7在其他Th亚型中在功能上是可有可无的。机械上,Hdac4与转录因子（TF）JunB相互作用，促进Th17标记基因如Il17a/f的转录激活。相反，Hdac7与TFAiolos和Smrt/Ncor1-Hdac3协同抑制因子来抑制Th17负调节因子的转录，包括Il2，在Th17细胞分化。通过药理学或遗传学方法抑制Hdac4/7有效减轻结肠炎小鼠模型中Th17细胞介导的肠道炎症。我们的研究揭示了HDAC4和HDAC7在Th17细胞分化过程中在调控有序基因转录方面具有独特但协同作用的分子机制。这些发现提示了靶向HDAC4/7治疗Th17相关炎性疾病的潜在治疗策略。如溃疡性结肠炎。
