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H3K4 di-methylation controls smooth muscle cell lineage identity and vascular homeostasis [CUT&Tag_H3K4me2_FLAG]

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE179217 | GEO | 2021/11/08

REPOSITORIES: GEO

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Project description:Recent genome wide association studies have identified a number of genes that contribute to the risk for coronary heart disease. One such gene, TCF21, encodes a basic-helix-loop-helix transcription factor believed to serve a critical role in the development of epicardial progenitor cells that give rise to coronary artery smooth muscle cells (SMC) and cardiac fibroblasts. Using reporter gene and immunolocalization studies with mouse and human tissues we have found that vascular TCF21 expression in the adult is restricted primarily to adventitial cells associated with coronary arteries and also medial SMC in the proximal aorta of mouse. Genome wide RNA-Seq studies in human coronary artery SMC (HCASMC) with siRNA knockdown found a number of putative TCF21 downstream pathways identified by enrichment of terms related to CAD, including “vascular disease,” “disorder of artery,” and “occlusion of artery” as well as disease-related cellular functions including “cellular movement,” and “cellular growth and proliferation.” In vitro studies in HCASMC demonstrated that TCF21 expression promotes proliferation and migration and inhibits SMC lineage marker expression. Detailed in situ expression studies with reporter gene and lineage tracing revealed that vascular wall cells expressing Tcf21 before disease initiation migrate into vascular lesions of ApoE-/- and Ldlr-/- mice. While Tcf21 lineage traced cells are distributed throughout the early lesions, in mature lesions they contribute to the formation of a subcapsular layer of cells, and others become associated with the fibrous cap. The lineage traced fibrous cap cells activate expression of SMC markers and growth factor receptor genes. Taken together, these data suggest that TCF21 may have a role regulating the differentiation state of SMC precursor cells that migrate into vascular lesions and contribute to the fibrous cap and more broadly, in view of the association of this gene with human CAD, provide evidence that these processes may be a mechanism for CAD risk attributable to the vascular wall.

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H3K4 di-methylation controls smooth muscle cell lineage identity and vascular homeostasis [CUT&Tag_H3K4me2_FLAG]

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