title: Interferon-γ resets muscle cell fate by stimulating the sequential recruitment of JARID2 and PRC2 to promoters to repress myogenesis.
abstract: The inflammatory cytokine interferon-γ (IFN-γ) orchestrates a diverse array of fundamental physiological processes. IFN-γ and the class II transactivator (CIITA) play essential roles in inhibiting muscle development during the inflammatory response. We describe the mechanism through which IFN-γ and CIITA inhibit myogenesis by repressing gene expression in muscle cells subjected to inflammation. In mice, the presence of increased amounts of circulating IFN-γ resulted in the increased abundance of Polycomb repressive complex 2 (PRC2) in muscle fibers, a tissue in which PRC2 is not normally present in the adult. We showed that CIITA first interacted with the Jumonji family protein JARID2, a noncatalytic subunit of PRC2, which caused an RNA polymerase II (RNAPII), phosphorylated at serine-5, to pause at target promoters. Additional subunits of the PRC2 complex, including the catalytic subunit EZH2, were then recruited in a JARID2-dependent manner that was concurrent with the loss of RNAPII and the methylation of Lys(27) of histone H3 (H3K27), which is associated with gene repression. IFN-γ and CIITA act to both promote the abundance of PRC2 subunits, which are not normally present during muscle differentation, and recruit the PRC2 complex to block myogenesis. Together, these data indicate that increased amounts of IFN-γ reset myogenic cell fate through a multistep mechanism that culminates in the recruitment of PRC2 to silence muscle-specific genes.
authors: Department of Biochemistry and Molecular Biology and Simmons Cancer Institute, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors: Priya
authors: P
authors: Londhe
authors: Judith K
authors: JK
authors: Davie
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D000071221:Enhancer of Zeste Homolog 2 Protein; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008745:Methylation / Q000187:drug effects; D024510:Muscle Development / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018008:Myogenin / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; C093650:Jarid2 protein, mouse; C083728:MHC class II transactivator protein; D018008:Myogenin; D009687:Nuclear Proteins; D015534:Trans-Activators; D012694:Serine; D007371:Interferon-gamma; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D012319:RNA Polymerase II