Class II transactivator (CIITA) mediates IFN-γ induced eNOS repression by enlisting SUV39H1

Publication date: Available online 1 February 2019

Source: Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms

Author(s): Xinyu Weng, Yuanyuan Zhang, Zilong Li, Liming Yu, Feng Xu, Mingming Fang, Lei Hou, Junbo Ge, Yong Xu

Abstract

Endothelial nitric oxide synthase (eNOS), selectively expressed in vascular endothelial cells, plays important roles in a range of biological and pathological processes. eNOS levels can be altered by extrinsic and intrinsic cues at the transcriptional level. Here we examined the epigenetic mechanism whereby the pro-inflammatory cytokine interferon gamma (IFN-γ) represses eNOS transcription. In response to IFN-γ treatment, there was a simultaneous down-regulation of eNOS expression and up-regulation of class II trans-activator (CIITA). Over-expression of CIITA directly repressed eNOS promoter while CIITA knockdown attenuated IFN-γ induced eNOS repression. Chromatin immunoprecipitation (ChIP) assay revealed that IFN-γ stimulation promoted CIITA occupancy on the proximal eNOS (−430/−168). Coincidently, CIITA recruitment on the eNOS promoter was paralleled by the disappearance of trimethylated histone H3K4 (H3K4Me3) and the enrichment of trimethylated H3K9 (H3K9Me3) with no significant changes in the levels of trimethylated H3K27 (H3K27Me3) or trimethylated H4K20 (H4K20Me3). In accordance, CIITA depletion was associated with the normalization of H3K4Me3 and H3K9Me3 on the eNOS promoter. Mechanistically, CIITA interacted with and enlisted the histone H3K9 trimethyltransferase SUV39H1 to the eNOS promoter to repress transcription. IFN-γ treatment augmented SUV39H1 expression and promoted SUV39H1 recruitment to the eNOS promoter in endothelial cells. Silencing of SUV39H1 abrogated eNOS repression by IFN-γ by erasing H3K9Me3 from the eNOS promoter. In conclusion, our data reveal a novel role for CIITA in endothelial cells and present SUV39H1 as a druggable target in the intervention of endothelial dysfunction.

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