YY1 regulates vascular resistance and blood pressure dynamics through epigenetic control of m6A RNA modifications in vascular smooth muscle cells

作者：Wen-Chu Ye, Wentao Gao, Chung Shun Ho, Lei Cui, James Y. Lau, Xiao Yu Tian, Bin Zhou, Kathy O. Lui · 发表于：Cardiovascular Research · 年份：2025 · DOI：10.1093/cvr/cvaf136 · 被引用次数：11 · 研究领域：RNA modifications and cancer、Epigenetics and DNA Methylation、Cancer-related gene regulation

AIMS: Recent genome-wide association study analysis has identified YY1 as a novel locus associated with blood pressure traits; however, whether YY1 directly controls vasoreactivity remains unknown. The principal function of vascular smooth muscle cells (VSMCs) is to contract, which is essential for regulating vascular tone, blood flow, and blood pressure. We hypothesized that YY1, a transcription factor, facilitates vascular function by epigenetically regulating gene expression in VSMCs. METHODS AND RESULTS: The effects of VSMC-specific YY1 loss were studied in mice. Lineage tracing, calcium imaging, and wire myography were performed to assess vasoreactivity. Genome-wide analysis through RNA-seq, ChIP-seq, m6A-seq, RNA immunoprecipitation, and transcript stability assays were conducted to evaluate gene expression and regulation. Co-immunoprecipitation was performed to study interactions between YY1 and chromatin regulators. AAV-mediated SM22-specific gene delivery was used to rescue vascular function in vivo. Contractile VSMCs were differentiated from human embryonic stem cells for in vitro experiments. Hypertension was induced in vivo using salt and L-NAME treatments. We demonstrate that vascular contraction and blood pressure are significantly reduced in Myh11CreER;Yy1fl/fl mice. YY1 does not regulate VSMC proliferation, survival, calcium entry, or membrane polarization in homeostasis. Integrative analyses of transcriptomics, epitranscriptomics, and epigenetics identified M...