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Epigenetic regulation of myogenic gene expression by heterochromatin protein 1 alpha.

ABSTRACT: Heterochromatin protein 1 (HP1) is an essential heterochromatin-associated protein typically involved in the epigenetic regulation of gene silencing. However, recent reports have demonstrated that HP1 can also activate gene expression in certain contexts including differentiation. To explore the role of each of the three mammalian HP1 family members (?, ? and ?) in skeletal muscle, their expression was individually disrupted in differentiating skeletal myocytes. Among the three isoforms of HP1, HP1? was specifically required for myogenic gene expression in myoblasts only. Knockdown of HP1? led to a defect in transcription of skeletal muscle-specific genes including Lbx1, MyoD and myogenin. HP1? binds to the genomic region of myogenic genes and depletion of HP1? results in a paradoxical increase in histone H3 lysine 9 trimethylation (H3K9me3) at these sites. JHDM3A, a H3K9 demethylase also binds to myogenic gene's genomic regions in myoblasts in a HP1?-dependent manner. JHDM3A interacts with HP1? and knockdown of JHDM3A in myoblasts recapitulates the decreased myogenic gene transcription seen with HP1? depletion. These results propose a novel mechanism for HP1?-dependent gene activation by interacting with the demethylase JHDM3A and that HP1? is required for maintenance of myogenic gene expression in myoblasts.

SUBMITTER: Sdek P

PROVIDER: S-EPMC3594309 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Epigenetic regulation of myogenic gene expression by heterochromatin protein 1 alpha.

Sdek Patima P Oyama Kyohei K Angelis Ekaterini E Chan Shing S SS Schenke-Layland Katja K MacLellan W Robb WR

PloS one 20130311 3

Heterochromatin protein 1 (HP1) is an essential heterochromatin-associated protein typically involved in the epigenetic regulation of gene silencing. However, recent reports have demonstrated that HP1 can also activate gene expression in certain contexts including differentiation. To explore the role of each of the three mammalian HP1 family members (α, β and γ) in skeletal muscle, their expression was individually disrupted in differentiating skeletal myocytes. Among the three isoforms of HP1, ...[more]

PMID: 23505487

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Project description:RATIONALE:The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability. OBJECTIVE:We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. METHODS AND RESULTS:We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and ?-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/?-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE-PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP. CONCLUSIONS:These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system.

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Epigenetic regulation of myogenic gene expression by heterochromatin protein 1 alpha.

Publications

Epigenetic regulation of myogenic gene expression by heterochromatin protein 1 alpha.

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