Link to dataset related to article "The epigenetic enzyme DOT1L orchestrates vascular smooth muscle cell-monocyte crosstalk and protects against atherosclerosis via the NF-κB pathway "

Link to dataset related to article "The epigenetic enzyme DOT1L orchestrates vascular smooth muscle cell-monocyte crosstalk and protects against atherosclerosis via the NF-κB pathway"

Abstract

Aims: 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.

Methods and results: 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.

Conclusion: 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.

与学术论文《表观遗传酶DOT1L通过NF-κB通路调控血管平滑肌细胞-单核细胞串扰并抵御动脉粥样硬化》相关的数据集链接

摘要

研究目的：赖氨酸79位点的组蛋白H3二甲基化是由端粒沉默干扰1样甲基转移酶（methyltransferase disruptor of telomeric silencing 1-like, DOT1L）特异性诱导的关键表观遗传标记。本研究旨在明确DOT1L是否可调控血管平滑肌细胞（vascular smooth muscle cell, VSMC）表型，并阐明其在体内外对动脉粥样硬化的影响及相关分子机制。

方法与结果：采用血小板衍生生长因子BB（platelet-derived growth factor BB, PDGF-BB）刺激血管平滑肌细胞进行基因表达筛选，鉴定出Dot1l为早期上调的表观遗传因子。对小鼠及人类动脉粥样硬化病灶的Dot1l表达进行检测，发现其特异性定位于血管平滑肌细胞区域。通过构建诱导型组织特异性敲除小鼠模型，并与载脂蛋白E敲除（Apolipoprotein E knockout, ApoE-/-）高脂饮食动脉粥样硬化模型杂交，特异性敲除血管平滑肌细胞中的Dot1l基因，以此评估Dot1l在动脉粥样硬化发病机制中的相关性。结果显示，Dot1l的失活可显著延缓疾病进展。联合RNA测序及H3K79me2染色质免疫共沉淀测序分析发现，DOT1L及其介导的H3K79me2标记可直接调控炎症核心调控因子NF-κB1与NF-κB2的转录，进而诱导CCL5与CXCL10的表达——这两种细胞因子在动脉粥样硬化发生发展中发挥关键作用。最后，本研究发现冠状动脉疾病与DOT1L基因的遗传变异存在相关性，特定的多态性位点与升高的mRNA表达水平相关。

结论：DOT1L在血管平滑肌细胞基因表达的表观遗传调控中发挥关键作用，参与动脉粥样硬化的发生发展。本研究结果表明DOT1L可作为血管疾病的潜在治疗靶点。