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THE EPIGENETIC ENZYME DOT1L ORCHESTRATES VSMC–MONOCYTE CROSSTALK TO PROTECT AGAINST ATHEROSCLEROSIS VIA THE NF-KB PATHWAY
Abstract
Background and Aims
Cardiovascular diseases are the principal cause of death and disability worldwide, and resulting in an estimated total economic burden of €210 billion. H3K79 dimethylation 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.
Methods
Gene expression screening of VSMCs, upon platelet-derived growth factor isoform BB (PDGF-BB) treatment, led us to identify DOT1L as an early upregulated 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-knockout mouse model crossed with the ApoE‑/- high-fat diet model of atherosclerosis.
Results
We found that inactivation of DOT1L significantly reduced atherosclerosis progression. By combining RNA sequencing and H3K79me2-chromatin immunoprecipitation, we then 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 induces the expression of CCL5 and CXCL10, both fundamentally involved in atherosclerosis development. Finally, a correlation between coronary artery disease and genetic variations in the DOT1L gene was found, since specific polymorphisms are associated with increased mRNA expression.
Conclusions
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.