title: The reorganisation of constitutive heterochromatin in differentiating muscle requires HDAC activity.
abstract: Constitutive heterochromatin was once thought to be remarkably stable in composition and transcriptionally inert, but has recently been shown to be surprisingly dynamic. Here, we show that terminal muscle differentiation results in a global reorganisation and spatial clustering of constitutive heterochromatin. This is accompanied by enhanced histone H3K9 and H4K20 tri-methylation across major satellite regions and increased levels of major and minor satellite-encoded transcripts. Histone deacetylase (HDAC) activity is known to be important for initiating muscle differentiation. However, here, we show that low doses of HDAC inhibitors applied after the onset of muscle differentiation prevent the spatial reorganisation of constitutive heterochromatin while allowing terminal differentiation to proceed. Under these conditions, HDAC inhibition interferes with histone methylation and blocks centromere clustering, but does not prevent the temporal expression of muscle regulatory factors or the accumulation of centromere-derived transcripts. The demonstration that HDAC activity is required for spatial relocation of centromeres in differentiating muscle provides a convenient system in which the molecular drivers of differentiation-induced chromosome repositioning can be dissected.
authors.affiliation: Lymphocyte Development Group, MRC, Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Rémi
authors.initials: R
authors.lastname: Terranova
authors.forename: Stephan
authors.initials: S
authors.lastname: Sauer
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Fisher
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002503:Centromere / Q000378:metabolism; D004276:DNA, Satellite / Q000235:genetics; D006570:Heterochromatin / Q000201:enzymology* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008745:Methylation; D051379:Mice; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000254:growth & development*; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D014158:Transcription, Genetic
chemical_list: D004276:DNA, Satellite; D006570:Heterochromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006655:Histone Deacetylases