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. Key question Epigenetics plays an important role in the regulation of atherosclerosis development. Its role in vascular smooth muscle cell biology and immune cell recruitment is not yet fully understood. Key finding Inhibition of the epigenetic enzyme disruptor of telomeric silencing 1-like (DOT1L) in vascular smooth muscle cells significantly reduces atherosclerosis progression, directly modulating Nfκb1 and Nfκb2 transcription. These genes are master regulators of inflammation, able to induce the expression of CCL5 and CXCL10 cytokines, which play a fundamental role in atherosclerosis development. Take home message DOT1L could be a promising therapeutic target since its inhibition reduces plaque progression.

Inhibition of the cardiac fibroblast-enriched histone methyltransferase Dot1L prevents cardiac fibrosis and cardiac dysfunction

“…Studies have shown that cardiac-specific conditional knockout of Dot1L in mice led to cardiac dilatation and postnatal lethality, confirmed that Dot1L activated key cardiac genes in cardiomyocyte differentiation and maturation by catalyzing different degrees of methylation on H3K79 [ 26 , 27 ], indicating the important regulation of Dot1L in heart development. It’s also demonstrated that Dot1L was involved in atherosclerosis development through NF-κB pathway [ 28 ]. Our study revealed that Dot1L was a critical component of pro-fibrotic signaling after MI.…”

Sox13 is a novel flow-sensitive transcription factor that prevents inflammation by repressing chemokine expression in endothelial cells

“…However, under the d-flow or SOX13 knockdown conditions, the SOX13-bound TF such as NF-κB could be released from SOX13 and bind to the CCL5 promoter, increasing its transcription. Interestingly, CCL5 and CXCL10 are known transcriptional targets of NF-κB family members (73). It would be interesting to test whether the loss of SOX13 would activate the NF-kB pathway leading to chemokine induction.…”

Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials

“…The correlation of epigenetics with cardiovascular diseases has primarily been identified in the function and expression of epigenetic-related enzymes found in cardiovascular diseases. To better understand the discovery and research history of epigenetics in cardiovascular diseases, it is helpful to review the timeline of epigenetics 43 – 63 (Fig. 4 ).…”