Epigenetic Regulation of Phenotypic Plasticity of Vascular Smooth Muscle Cells

血管平滑肌细胞表型可塑性的表观遗传调控

基本信息

  • 批准号:
    RGPIN-2020-04592
  • 负责人:
  • 金额:
    $ 2.62万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2022
  • 资助国家:
    加拿大
  • 起止时间:
    2022-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Vascular smooth muscle cells (SMCs) are not terminally differentiated and have phenotypic plasticity: differentiated, contractile SMCs can undergo dedifferentiation and become synthetic and proliferative, and vice versa. Myocardin, a transcriptional coactivator of serum response factor (SRF), controls the expression of SMC contractile proteins and microRNAs (miRs) to promote SMC differentiation and inhibit cell proliferation. Many factors including hormones, growth factors and cytokines regulate SMC plasticity, but how they trigger intracellular signaling to confer phenotypic switching is poorly understood. Evidence suggests that epigenetic modification participates in SMC phenotype regulation. DNA methylation, for example, inhibits myocardin gene expression. DNA methylation and demethylation are catalyzed by methyltransferases (DNMT1, 3A, 3B) and ten-eleven translocation (TET1, 2, 3) enzymes, respectively. Myocardin is associated with demethylation of its target genes, in which TET2 binds to CArG boxes in the promoters. However, the exact mechanisms underlying epigenetic regulation of SMC phenotypes remain largely unknown. Rationale and hypothesis. Our preliminary results showed a role for DNA methylation in myocardin expression and functions. Our previous findings also revealed myocardin induction of miR-1 expression and inhibition of cell proliferation. Therefore, we hypothesize that myocardin gene methylation and demethylation determines myocardin gene expression and that myocardin also induces DNA demethylation of its target genes, driving SMC differentiation and inhibiting cell proliferation. Objectives. To test the above hypotheses, we set up two aims over 5 years: 1) Investigate the roles for myocardin gene methylation and demethylation in SMC phenotypic plasticity. We expect to discover or reveal the specific DNMTs and TETs that dictate the DNA methylation level of the myocardin gene, contributing to the regulation of SMC phenotypic plasticity. 2) Determine how myocardin modulates DNA methylation of its target genes, including SM contractile proteins and miRs. We expect to reveal myocardin induction of demethylation of its target genes, such as SM contractile proteins and miRs, and the underlying mechanisms. Significance. Our studies will uncover a novel epigenetic mechanism underlying SMC phenotypic plasticity, representing a major advancement in vascular biology.
血管平滑肌细胞(SMC)不是终末分化的,并且具有表型可塑性:分化的收缩性SMC可以经历去分化并变得合成和增殖,反之亦然。心肌细胞因子(Myocardin)是血清反应因子(SRF)的转录辅激活因子,通过调控SMC收缩蛋白和microRNA(miRs)的表达,促进SMC分化,抑制细胞增殖。许多因素,包括激素,生长因子和细胞因子调节SMC的可塑性,但他们如何触发细胞内信号传递,赋予表型转换知之甚少。有证据表明,表观遗传修饰参与SMC表型调控。例如,DNA甲基化抑制心肌蛋白基因表达。DNA甲基化和去甲基化分别由甲基转移酶(DNMT 1,3A,3B)和10 - 11易位酶(TET 1,2,3)催化。Myocardin与其靶基因的去甲基化相关,其中TET 2结合启动子中的CArG盒。然而,SMC表型的表观遗传调控的确切机制在很大程度上仍然未知。 理由和假设。我们的初步结果表明,DNA甲基化在心肌蛋白的表达和功能中的作用。我们先前的研究结果也揭示了心肌素诱导miR-1表达和抑制细胞增殖。因此,我们推测,myocardin基因甲基化和去甲基化决定myocardin基因的表达,myocardin也诱导其靶基因的DNA去甲基化,驱动SMC分化和抑制细胞增殖。 目标.为了验证上述假设,我们在5年内设立了两个目标:1)研究myocardin基因甲基化和去甲基化在SMC表型可塑性中的作用。我们期望发现或揭示特定的DNMTs和TcR,决定了myocardin基因的DNA甲基化水平,有助于SMC表型可塑性的调节。2)确定myocardin如何调节其靶基因的DNA甲基化,包括SM收缩蛋白和miR。我们希望揭示心肌素诱导其靶基因,如SM收缩蛋白和miR的去甲基化及其潜在机制。意义我们的研究将揭示一种新的表观遗传学机制的基础SMC表型可塑性,代表了血管生物学的重大进展。

项目成果

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Zheng, XiLong其他文献

Zheng, XiLong的其他文献

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{{ truncateString('Zheng, XiLong', 18)}}的其他基金

Epigenetic Regulation of Phenotypic Plasticity of Vascular Smooth Muscle Cells
血管平滑肌细胞表型可塑性的表观遗传调控
  • 批准号:
    RGPIN-2020-04592
  • 财政年份:
    2021
  • 资助金额:
    $ 2.62万
  • 项目类别:
    Discovery Grants Program - Individual
Epigenetic Regulation of Phenotypic Plasticity of Vascular Smooth Muscle Cells
血管平滑肌细胞表型可塑性的表观遗传调控
  • 批准号:
    RGPIN-2020-04592
  • 财政年份:
    2020
  • 资助金额:
    $ 2.62万
  • 项目类别:
    Discovery Grants Program - Individual
SRF-independent roles of Myocardin in differentiation of vascular smooth muscle cells
心肌素在血管平滑肌细胞分化中的 SRF 独立作用
  • 批准号:
    RGPIN-2017-04889
  • 财政年份:
    2017
  • 资助金额:
    $ 2.62万
  • 项目类别:
    Discovery Grants Program - Individual

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