The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation.

By G. Caretti, Monica Di Padova, B. Micales, G. Lyons, V. Sartorelli. Genes & Development, 2004

636 citations recorded by the source corpus.

The Ezh2 protein endows the Polycomb PRC2 and PRC3 complexes with histone lysine methyltransferase (HKMT) activity that is associated with transcriptional repression. We report that Ezh2 expression was developmentally regulated in the myotome compartment of mouse somites and that its down-regulation coincided with activation of muscle gene expression and differentiation of satellite-cell-derived myoblasts. Increased Ezh2 expression inhibited muscle differentiation, and this property was conferred by its SET domain, required for the HKMT activity. In undifferentiated myoblasts, endogenous Ezh2 was associated with the transcriptional regulator YY1. Both Ezh2 and YY1 were detected, with the deacetylase HDAC1, at genomic regions of silent muscle-specific genes. Their presence correlated with methylation of K27 of histone H3. YY1 was required for Ezh2 binding because RNA interference of YY1 abrogated chromatin recruitment of Ezh2 and prevented H3-K27 methylation. Upon gene activation, Ezh2, HDAC1, and YY1 dissociated from muscle loci, H3-K27 became hypomethylated and MyoD and SRF were recruited to the chromatin. These findings suggest the existence of a two-step activation mechanism whereby removal of H3-K27 methylation, conferred by an active Ezh2-containing protein complex, followed by recruitment of positive transcriptional regulators at discrete genomic loci are required to promote muscle gene expression and cell differentiation.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1a812735dbcff57108541673b25fee3fb6419505

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Citations in the corpus

Polycomb silencers control cell fate, development and cancer (2006, result): “This model is consistent with previous results, suggesting a similar role for PcGs in muscle and germ cell terminal differentiation processe”
Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. (2010, neutral): “Similar observations have been reported for many somatic tissues (Ezhkova et al., 2009; Caretti et al., 2004; Hirabayashi et al., 2009; Zencak et al., 2005).”
MicroRNAs in development and disease. (2011, background): “In accordance, Ezh2 is present in myotomes and is downregulated upon differentiation, allowing MyoD to bind to and activate muscle genes (77).”
Ezh2 Orchestrates Gene Expression for the Stepwise Differentiation of Tissue-Specific Stem Cells (2009, background): “Thus, we speculated that triMeK27-H3 marks on EDC genes in WT basal cells may interfere with AP1 recruitment, as it has been shown for Myod1 in muscle cells in vitro (Caretti et al., 2004).”
MicroRNAs: key regulators of stem cells (2009, background): “This paves the way for transcriptional activation of these gene”
The Polycomb Group Protein Suz12 Is Required for Embryonic Stem Cell Differentiation (2007, positive): “imental results using myoblasts (10), ES cells (4, 21), and”
Polycomb group proteins: navigators of lineage pathways led astray in cancer (2009, neutral): “Several mammalian transcription factors physically associate with PcG proteins, such as YY1 (Ref”
Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. (2006, background): “This model is consistent with previous results, suggesting a similar role for the PcGs in muscle and germ cell terminal differentiation processes (Caretti et al. 2004; Chen et al. 2005) and predicts that this is a general phenomenon.”
Mechanisms of Polycomb gene silencing: knowns and unknowns (2009, background): “Indeed, YY1 knockdown dislodges the PRC2 subunit enhancer of Zeste homologue 2 ( EZH2 ) and removes methylated H3K27 from target genes in mouse myoblast”
EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. (2008, background): “…development, PRC2 is required for diverse physiological functions including B lymphoid development, myogenic differentiation, imprinted X chromosome inactivation, and reprogramming of migrating primordial germ cells (Caretti et al., 2004; Kalantry et al., 2006; Seki et al., 2007; Su et al., 2003).”
Covalent modifications of histones during development and disease pathogenesis (2007, background): “Other SET domain–containing histone methyltransferases are involved in muscle development, with Ezh2 regulating muscle gene expression and skeletal muscle differentiatio”
The Polycomb Complex PRC2 and its Mark in Life (2011, background): “, PRC2 inactivation also promotes differentiation during myogenesis and epidermis formatio”