表观遗传学
基因沉默
细胞生物学
染色质免疫沉淀
血管平滑肌
基因表达
基因表达调控
生物
转录因子
染色质
组蛋白
表观遗传学
串扰
癌症研究
DNA甲基化
基因
遗传学
发起人
内分泌学
物理
平滑肌
光学
作者
Floriana Maria Farina,Simone Serio,Ignacio Fernando Hall,Stefania Zani,Giada Andrea Cassanmagnago,Montserrat Climent,Efrem Civilini,Gianluigi Condorelli,Manuela Quintavalle,Leonardo Elia
标识
DOI:10.1093/eurheartj/ehac097
摘要
Histone H3 dimethylation at lysine 79 is a key epigenetic mark uniquely induced by methyltransferase disruptor of telomeric silencing 1-like (DOT1L). We aimed to determine whether DOT1L modulates vascular smooth muscle cell (VSMC) phenotype and how it might affect atherosclerosis in vitro and in vivo, unravelling the related mechanism.Gene expression screening of VSMCs stimulated with the BB isoform of platelet-derived growth factor led us to identify Dot1l as an early up-regulated epigenetic factor. Mouse and human atherosclerotic lesions were assessed for Dot1l expression, which resulted specifically localized in the VSMC compartment. The relevance of Dot1l to atherosclerosis pathogenesis was assessed through deletion of its gene in the VSMCs via an inducible, tissue-specific knock-out mouse model crossed with the ApoE-/- high-fat diet model of atherosclerosis. We found that the inactivation of Dot1l significantly reduced the progression of the disease. By combining RNA- and H3K79me2-chromatin immunoprecipitation-sequencing, we found that DOT1L and its induced H3K79me2 mark directly regulate the transcription of Nf-κB-1 and -2, master modulators of inflammation, which in turn induce the expression of CCL5 and CXCL10, cytokines fundamentally involved in atherosclerosis development. Finally, a correlation between coronary artery disease and genetic variations in the DOT1L gene was found because specific polymorphisms are associated with increased mRNA expression.DOT1L plays a key role in the epigenetic control of VSMC gene expression, leading to atherosclerosis development. Results identify DOT1L as a potential therapeutic target for vascular diseases.
科研通智能强力驱动
Strongly Powered by AbleSci AI