UHRF1 epigenetically orchestrates smooth muscle cell plasticity in arterial disease
Leonardo Elia, Paolo Kunderfranco, Pierluigi Carullo, Marco Vacchiano, Floriana Maria Farina, Ignacio Fernando Hall, Stefano Mantero, Cristina Panico, Roberto Papait, Gianluigi Condorelli, Manuela Quintavalle
Leonardo Elia, Paolo Kunderfranco, Pierluigi Carullo, Marco Vacchiano, Floriana Maria Farina, Ignacio Fernando Hall, Stefano Mantero, Cristina Panico, Roberto Papait, Gianluigi Condorelli, Manuela Quintavalle
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Research Article Cell biology Vascular biology

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.

Authors

Leonardo Elia, Paolo Kunderfranco, Pierluigi Carullo, Marco Vacchiano, Floriana Maria Farina, Ignacio Fernando Hall, Stefano Mantero, Cristina Panico, Roberto Papait, Gianluigi Condorelli, Manuela Quintavalle

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Figure 8

Effects of Uhrf1 absence in vitro.

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Effects of Uhrf1 absence in vitro. (A) Hierarchical clustering heat map ...
(A) Hierarchical clustering heat map of 615 probes differentially expressed between shUHRF1 and shSCR (P ≤ 0.1, –1.3 ≤ fold-change ≥ 1.3). (B) Dot plot, with blue dots representing downregulated protein-coding genes (263) and yellow dots representing upregulated protein-coding genes (278) in shUHRF1 and shSCR cells. (C) ChIP assay showing UHRF1 enrichment at the Tgfβ2 and Tgfβr1 promoters in proliferating VSMCs (cells cultured with 10% FBS). Data are presented as mean relative enrichment over input ± SD of 3 biological repeats. (D) Methyl ChIP assay showing reduced methylation at the Tgfβ2 and Tgfβr1 promoters in the absence of UHRF1 (cells cultured with 10% FBS). Data are presented as mean relative enrichment over input ± SD of 3 biological repeats. (E) Representative Western blots showing activation of the canonical TGF-β pathway in Uhrf1-silenced VSMCs. Error bars indicate SD. To compare means, we used unpaired 2-tailed Student’s t test in C and 1-way ANOVA with Tukey’s multiple comparisons t test in D. #P < 0.05 (P value is only adjusted in D).