H3K4 di-methylation controls smooth muscle cell lineage identity and vascular homeostasis [RNAseq]

Epigenetic control of lineage-specific gene expression is essential for cell differentiation, acquisition of specialized functions, and tissue homeostasis. Here, we uncovered a unique epigenetic pathway critical for governing lineage identity in cells presenting milieu-dependent phenotypic modulation in adult organisms, by using vascular smooth muscle cells (SMC) as a model of highly specialized and differentiated cell type retaining phenotypic plasticity. We found that the histone modification H3K4me2 is essential for the maintenance of vascular SMC lineage identity and functions by performing H3K4me2 demethylation selectively on a SMC lineage-specific subset of genes. Removal of H3K4me2 on the myocardin-regulated genes led to a marked loss of contractility and alteration in SMC adaptive response capacities during vascular remodeling. Rather than presenting intrinsic gene activation properties, H3K4me2 serves as a stable preferential hub for the dynamic recruitment of the DNA methylcytosine dioxygenase Ten-Eleven Translocation 2 (TET2). Besides the SMC contractile apparatus, the H3K4me2/TET2 complex controls the expression of miR-145, a central microRNA promoting SMC differentiation and participation in vascular remodeling. Finally, H3K4me2 editing induced a profound loss of SMC lineage identity and gain of plasticity, characterized by the redistribution of H3K4me2 on genes associated with stemness and developmental programs and the greater ability of H3K4me2 edited SMC to transdifferentiate into other lineages. These studies identified H3K4me2 as a central epigenetic mechanism controlling lineage identity and cell-specific specialized functions. Our findings may have broad implications for the understanding of mechanisms controlling multiple plastic cell type behaviors and functions in various pathophysiological processes.谱系特异性基因表达的表观遗传调控，对于细胞分化、特化功能获得以及组织稳态维持至关重要。本研究以血管平滑肌细胞（vascular smooth muscle cells, SMC）——一种兼具高度特化分化状态与表型可塑性的成熟细胞类型——为模型，揭示了一条独特的表观遗传通路，该通路对于调控成年机体中存在微环境依赖性表型调控的细胞的谱系身份至关重要。我们发现，组蛋白修饰H3K4me2通过选择性对SMC谱系特异性基因子集进行H3K4me2去甲基化，对维持血管SMC的谱系身份与功能不可或缺。在心肌素调控的基因上移除H3K4me2，会导致血管重构过程中平滑肌细胞收缩能力显著丧失，以及其适应性应答能力发生改变。H3K4me2并非具备内在的基因激活特性，而是作为稳定的优先结合枢纽，动态招募DNA甲基胞嘧啶双加氧酶Ten-Eleven Translocation 2（TET2）。除SMC收缩装置外，H3K4me2-TET2复合物还调控miR-145的表达——这是一种核心微小RNA，可促进SMC分化并参与血管重构过程。最后，H3K4me2编辑会导致SMC谱系身份显著丧失并获得可塑性，具体表现为H3K4me2在与干细胞性及发育程序相关的基因上发生重新分布，且经H3K4me2编辑的SMC向其他谱系转分化的能力显著增强。本研究确认H3K4me2是调控谱系身份与细胞特异性特化功能的核心表观遗传机制。我们的发现对于理解多种病理生理过程中调控可塑性细胞类型行为与功能的机制，具有广泛的启示意义。