title: Genome-wide remodeling of the epigenetic landscape during myogenic differentiation.
abstract: We have examined changes in the chromatin landscape during muscle differentiation by mapping the genome-wide location of ten key histone marks and transcription factors in mouse myoblasts and terminally differentiated myotubes, providing an exceptionally rich dataset that has enabled discovery of key epigenetic changes underlying myogenesis. Using this compendium, we focused on a well-known repressive mark, histone H3 lysine 27 trimethylation, and identified novel regulatory elements flanking the myogenin gene that function as a key differentiation-dependent switch during myogenesis. Next, we examined the role of Polycomb-mediated H3K27 methylation in gene repression by systematically ablating components of both PRC1 and PRC2 complexes. Surprisingly, we found mechanistic differences between transient and permanent repression of muscle differentiation and lineage commitment genes and observed that the loss of PRC1 and PRC2 components produced opposing differentiation defects. These phenotypes illustrate striking differences as compared to embryonic stem cell differentiation and suggest that PRC1 and PRC2 do not operate sequentially in muscle cells. Our studies of PRC1 occupancy also suggested a "fail-safe" mechanism, whereby PRC1/Bmi1 concentrates at genes specifying nonmuscle lineages, helping to retain H3K27me3 in the face of declining Ezh2-mediated methyltransferase activity in differentiated cells.
authors.affiliation: Department of Pathology and Cancer Institute, New York University School of Medicine, 522 First Avenue, Smilow Research Building 1104, New York, NY 10016, USA.
authors.forename: Patrik
authors.initials: P
authors.lastname: Asp
authors.forename: Roy
authors.initials: R
authors.lastname: Blum
authors.forename: Vasupradha
authors.initials: V
authors.lastname: Vethantham
authors.forename: Fabio
authors.initials: F
authors.lastname: Parisi
authors.forename: Mariann
authors.initials: M
authors.lastname: Micsinai
authors.forename: Jemmie
authors.initials: J
authors.lastname: Cheng
authors.forename: Christopher
authors.initials: C
authors.lastname: Bowman
authors.forename: Yuval
authors.initials: Y
authors.lastname: Kluger
authors.forename: Brian David
authors.initials: BD
authors.lastname: Dynlacht
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology; D044127:Epigenesis, Genetic; D055106:Genome-Wide Association Study; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008745:Methylation; D051379:Mice; D024510:Muscle Development; D009132:Muscles / Q000502:physiology; D010641:Phenotype; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D006657:Histones; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D008239:Lysine