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
• 负责人: Zheng, XiLong
• 金额: $ 2.62万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717125
• 关键词: Epigenetic; Regulation; Phenotypic; Plasticity; Vascular

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）没有终止分化，具有表型可塑性：分化的收缩SMC可以进行去分化，并变得合成和增殖，反之亦然。心肌素是血清反应因子（SRF）的转录共激活因子，控制了SMC收缩蛋白和microRNA（MIR）的表达，以促进SMC分化并抑制细胞增殖。包括激素，生长因子和细胞因子在内的许多因素都调节了SMC的可塑性，但是它们如何触发细胞内信号传导赋予表型转换。 证据表明表观遗传修饰参与了SMC表型调节。例如，DNA甲基化抑制心肌素基因表达。 DNA甲基化和脱甲基化分别通过甲基转移酶（DNMT1、3A，3B）和十个易位（TET1、2、3）酶催化。心肌素与其靶基因的脱甲基化有关，其中TET2与启动子中的carg盒结合。但是，SMC表型的表观遗传调节的确切机制在很大程度上尚不清楚。 理由和假设。我们的初步结果显示了DNA甲基化在心肌素表达和功能中的作用。我们以前的发现还表明，心肌蛋白诱导miR-1表达和细胞增殖的抑制作用。因此，我们假设心肌蛋白基因甲基化和脱甲基化决定了心肌素基因的表达，并且心肌也会诱导其靶基因的DNA脱甲基化，从而驱动SMC分化并抑制细胞增殖。 目标。为了检验上述假设，我们在5年内设定了两个目标： 1）研究心肌蛋白基因甲基化和脱甲基在SMC表型可塑性中的作用。我们期望发现或揭示决定肌动蛋白基因DNA甲基化水平的特定DNMT和TET，这有助于调节SMC表型可塑性。 2）确定心肌如何调节其靶基因的DNA甲基化，包括SM收缩蛋白和miR。我们希望揭示其靶基因脱甲基的肌动蛋白诱导，例如SM收缩蛋白和miR，以及潜在的机制。 意义。我们的研究将发现SMC表型可塑性的一种新型的表观遗传机制，代表了血管生物学的主要进步。