The histone chaperone Spt6 coordinates histone H3K27 demethylation and myogenesis
ABSTRACT Histone chaperones affect chromatin structure and gene expression through interaction with histones and RNA polymerase II (PolII). Here, we report that the histone chaperone Spt6 counteracts H3K27me3, an epigenetic mark deposited by the Polycomb Repressive Complex 2 (PRC2) and associated with transcriptional repression. By regulating proper engagement and function of the H3K27 demethylase KDM6A (UTX), Spt6 effectively promotes H3K27 demethylation, muscle gene expression, and cell differentiation. ChIP-Seq experiments reveal an extensive genome-wide overlap of Spt6, PolII, and KDM6A at transcribed regions that are devoid of H3K27me3. Mammalian cells and zebrafish embryos with reduced Spt6 display increased H3K27me3 and diminished expression of the master regulator MyoD, resulting in myogenic differentiation defects. As a confirmation for an antagonistic relationship between Spt6 and H3K27me3, inhibition of PRC2 permits MyoD re-expression in myogenic cells with reduced Spt6. Our data indicate that, through cooperation with PolII and KDM6A, Spt6 orchestrates removal of H3K27me3, thus controlling developmental gene expression and cell differentiation.
SourceAvailable from: Glenda Comai[Show abstract] [Hide abstract]
ABSTRACT: Since the seminal discovery of the cell-fate regulator Myod, studies in skeletal myogenesis have inspired the search for cell-fate regulators of similar potential in other tissues and organs. It was perplexing that a similar transcription factor for other tissues was not found; however, it was later discovered that combinations of molecular regulators can divert somatic cell fates to other cell types. With the new era of reprogramming to induce pluripotent cells, the myogenesis paradigm can now be viewed under a different light. Here, we provide a short historical perspective and focus on how the regulation of skeletal myogenesis occurs distinctly in different scenarios and anatomical locations. In addition, some interesting features of this tissue underscore the importance of reconsidering the simple-minded view that a single stem cell population emerges after gastrulation to assure tissuegenesis. Notably, a self-renewing long-term Pax7+ myogenic stem cell population emerges during development only after a first wave of terminal differentiation occurs to establish a tissue anlagen in the mouse. How the future stem cell population is selected in this unusual scenario will be discussed. Recently, a wealth of information has emerged from epigenetic and genome-wide studies in myogenic cells. Although key transcription factors such as Pax3, Pax7, and Myod regulate only a small subset of genes, in some cases their genomic distribution and binding are considerably more promiscuous. This apparent nonspecificity can be reconciled in part by the permissivity of the cell for myogenic commitment, and also by new roles for some of these regulators as pioneer transcription factors acting on chromatin state.Current Topics in Developmental Biology 01/2014; 110C:1-73. DOI:10.1016/B978-0-12-405943-6.00001-4 · 4.21 Impact Factor
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ABSTRACT: Skeletal muscle regeneration in the adult (de novo myogenesis) depends on a resident population of muscle stem cells (satellite cells) which are normally quiescent. In response to injury or stress, satellite cells are activated and expand as myoblast cells that will differentiate and fuse to form new muscle fibers or will return to quiescence to maintain the stem cell pool (self-renewal). Satellite cell-dependent myogenesis is a well-characterized multi-step process orchestrated by muscle-specific transcription factors, such as Pax3/Pax7 and members of the MyoD family of muscle regulatory factors, and epigenetically controlled by mechanisms such as DNA methylation, covalent modification of histones and non-coding RNAs. Recent results from next-generation genome-wide sequencing have increased our understanding about the highly intricate layers of epigenetic regulation involved in satellite cell maintenance, activation, differentiation, and self-renewal, and their cross-talk with the muscle-specific transcriptional machinery.This article is protected by copyright. All rights reserved.FEBS Journal 09/2014; DOI:10.1111/febs.13065 · 3.99 Impact Factor
Article: Myogenesis in the genomics era[Show abstract] [Hide abstract]
ABSTRACT: Skeletal myogenesis is the process of formation of the muscles that enable movement and breathing. Muscles form after the fate determination and differentiation of precursor cells. Being an extraordinarily complex process, myogenesis is regulated at multiple levels, and transcriptional regulation naturally plays a big part in the making of muscle. A significant part of what we know today of the transcriptional regulatory networks overseeing myogenesis comes from large-scale functional genomics studies. The objective of this review is to provide an overview of the various genomics techniques that have been employed over the years to understand myogenic regulation, to give a sense of the degree of understanding they have provided us up to now, and to highlight the next challenges to be overcome. Copyright © 2015. Published by Elsevier Ltd.Journal of Molecular Biology 02/2015; 11. DOI:10.1016/j.jmb.2015.02.009 · 3.96 Impact Factor