UHRF1 epigenetically orchestrates smooth muscle cell plasticity in arterial disease

Abstract

Adult vascular smooth muscle cells (VSMCs) dedifferentiate in response to extracellular cues such as vascular damage and inflammation. Dedifferentiated VSMCs are proliferative, migratory, less contractile, and can contribute to vascular repair as well as to cardiovascular pathologies such as intimal hyperplasia/restenosis in coronary artery and arterial aneurysm. We here demonstrate the role of ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) as an epigenetic master regulator of VSMC plasticity. UHRF1 expression correlated with the development of vascular pathologies associated with modulation of noncoding RNAs, such as microRNAs. miR-145 - pivotal in regulating VSMC plasticity, which is reduced in vascular diseases - was found to control Uhrf1 mRNA translation. In turn, UHRF1 triggered VSMC proliferation, directly repressing promoters of cell-cycle inhibitor genes (including p21 and p27) and key prodifferentiation genes via the methylation of DNA and histones. Local vascular viral delivery of Uhrf1 shRNAs or Uhrf1 VSMC-specific deletion prevented intimal hyperplasia in mouse carotid artery and decreased vessel damage in a mouse model of aortic aneurysm. Our study demonstrates the fundamental role of Uhrf1 in regulating VSMC phenotype by promoting proliferation and dedifferentiation. UHRF1 targeting may hold therapeutic potential in vascular pathologies.

Angioplasty-induced epigenomic remodeling entails BRD4 and EZH2 hierarchical regulations

“…Here we found that while EZH2 (or EZH1) loss-of-function reduced, their gain-offunction increased Uhrf1 mRNA ( Figure 7B). Thus, we identified UHRF1 as a novel target of EZH1/2 functional regulation, a finding consistent with the recently reported positive role of UHRF1 in SMC proliferation/migration and injury-induced IH 30 .…”

“…Further attracting our interest, ChIPseq signal for H3K27ac at Uhrf1 magnified after injury ( Figure 7A). Consistently, recent reports indicated that UHRF1 functionally associates with histone methylation and acetylation 29 , and its upregulation in injured arteries promotes SMC proliferation and IH 30 . Interestingly, Ezh2 and Uhrf1 were reported to be in the same gene network both promoting keratinocyte self-renewal 31 , yet their epigenomic relationship was not known.…”

“…Other than a cytokinetic factor, UHRF1 is a multifunctional epigenetic reader without a previously recognized functional connection with EZH2 29 . Very recently, UHRF1 was reported to play a critical role in IH 30 , and in another study found to associate with both methylation and acetylation histone marks 29 . Thus, its potential functional interplay with BRD4 and EZH2 in the IH context deserves a new project to explore.…”

Histone methylation and vascular biology

“…PRISM interacted with G9a histone methyltransferase and class I histone deacetylases to induce genes associated with the proliferative smooth muscle phenotype while repressing regulators of differentiation, including myocardin and GATA-6 in primary VSMCs [61]. H3K27me3 and H3K4me2 were reportedly involved in neointima formation by regulating Myh11, Acta2, Cnn1, and Sm22 or Vcam-1 expression [62,63].…”

Epigenetic Signalling and RNA Regulation in Cardiovascular Diseases

“…Additionally, miR-145 regulates ubiquitin-like containing PHD and RING finger domains 1 (UHRF1), which interacts with DNA methyltransferase 1 (DNMT1), suggesting an indirect link between miRNA modulation and DNA methylation [67]. DNMT1 was found to methylate miR-145 promoter realizing a negative feedback loop [66] Moreover, low levels of miR145 allow the transduction of UTRF1 which is activator of DNMT1 that in turn methylates miR145 promoter activating a negative feedback loop.…”