Chromatin regulated interchange between polycomb repressive complex 2 (PRC2)-Ezh2 and PRC2-Ezh1 complexes controls myogenin activation in skeletal muscle cells

Abstract

BackgroundPolycomb group (PcG) genes code for chromatin multiprotein complexes that are responsible for maintaining gene silencing of transcriptional programs during differentiation and in adult tissues. Despite the large amount of information on PcG function during development and cell identity homeostasis, little is known regarding the dynamics of PcG complexes and their role during terminal differentiation.ResultsWe show that two distinct polycomb repressive complex (PRC)2 complexes contribute to skeletal muscle cell differentiation: the PRC2-Ezh2 complex, which is bound to the myogenin (MyoG) promoter and muscle creatine kinase (mCK) enhancer in proliferating myoblasts, and the PRC2-Ezh1 complex, which replaces PRC2-Ezh2 on MyoG promoter in post-mitotic myotubes. Interestingly, the opposing dynamics of PRC2-Ezh2 and PRC2-Ezh1 at these muscle regulatory regions is differentially regulated at the chromatin level by Msk1 dependent methyl/phospho switch mechanism involving phosphorylation of serine 28 of the H3 histone (H3S28ph). While Msk1/H3S28ph is critical for the displacement of the PRC2-Ezh2 complex, this pathway does not influence the binding of PRC2-Ezh1 on the chromatin. Importantly, depletion of Ezh1 impairs muscle differentiation and the chromatin recruitment of MyoD to the MyoG promoter in differentiating myotubes. We propose that PRC2-Ezh1 is necessary for controlling the proper timing of MyoG transcriptional activation and thus, in contrast to PRC2-Ezh2, is required for myogenic differentiation.ConclusionsOur data reveal another important layer of epigenetic control orchestrating skeletal muscle cell terminal differentiation, and introduce a novel function of the PRC2-Ezh1 complex in promoter setting.

Epigenetic Control of the Bone-master Runx2 Gene during Osteoblast-lineage Commitment by the Histone Demethylase JARID1B/KDM5B

“…Alternatively, an additional contribution to the H3K27me3 enrichment at the Runx2 promoter by a PRC2 complex carrying EZH1 as the catalytic subunit needs to be considered. It has been shown that during myoblast differentiation nuclear PRC2-EZH1 concentrations are drastically increased (55), where this complex is found to mediate important regulatory functions. Remarkably, the increased in H3K27me3 enrichment at the Runx2 P1 promoter during myoblast differentiation occurs in the presence of the H3K27me3 demethylase UTX.…”

Roles of enhancer of zeste homolog 2: From skeletal muscle differentiation to rhabdomyosarcoma carcinogenesis

“…39 Surprisingly, during muscle differentiation, several evidences showed a role of EZH1 in transcriptional activation. 40,41 PRC1 and PRC2 are able to induce gene silencing independently by each other, 42,43 or by a more common synergistic mechanism. Establishment of H3K27me3 by PRC2 complex induces the recruitment of PRC1.…”

New insights into the epigenetic control of satellite cells

“…Indeed, Ezh2-mediated H3K27me3 marks are specifically present on genes associated with alternative lineage selection, although Ezh2 dos not suppress terminal differentiation into skeletal muscle [80] . In contrast to PRC2-Ezh2, PRC2-Ezh1 is required for the myogenic differentiation of SCs; specifically, PRC2-Ezh1 replaces PRC2-Ezh2 on the myogenin promoter to regulate the appropriate timing of the transcriptional activation of myogenin [81] . When SCs differentiate, HDAC1 downregulation and pRb hypo-phosphorylation occurs, enabling the formation of the pRb-HDAC1 complex in differentiated myotubes.…”