title: Differential modulation of the oligodendrocyte transcriptome by sonic hedgehog and bone morphogenetic protein 4 via opposing effects on histone acetylation.
abstract: Differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes is regulated by the interplay between extrinsic signals and intrinsic epigenetic determinants. In this study, we analyze the effect that the extracellular ligands sonic hedgehog (Shh) and bone morphogenetic protein 4 (BMP4), have on histone acetylation and gene expression in cultured OPCs. Shh treatment favored the progression toward oligodendrocytes by decreasing histone acetylation and inducing peripheral chromatin condensation. BMP4 treatment, in contrast, inhibited the progression toward oligodendrocytes and favored astrogliogenesis by favoring global histone acetylation and retaining euchromatin. Pharmacological treatment or silencing of histone deacetylase 1 (Hdac1) or histone deacetylase 2 (Hdac2) in OPCs did not affect BMP4-dependent astrogliogenesis, while it prevented Shh-induced oligodendrocyte differentiation and favored the expression of astrocytic genes. Transcriptional profiling of treated OPCs, revealed that BMP4-inhibition of oligodendrocyte differentiation was accompanied by increased levels of Wnt (Tbx3) and Notch-target genes (Jag1, Hes1, Hes5, Hey1, and Hey2), decreased recruitment of Hdac and increased histone acetylation at these loci. Similar upregulation of Notch-target genes and increased histone acetylation were observed in the corpus callosum of mice infused with BMP4 during cuprizone-induced demyelination. We conclude that Shh and Bmp4 differentially regulate histone acetylation and chromatin structure in OPCs and that BMP4 acts as a potent inducer of gene expression, including Notch and Wnt target genes, thereby enhancing the crosstalk among signaling pathways that are known to inhibit myelination and repair.
authors.affiliation: Department of Neuroscience, Friedman Brain Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Muzhou
authors.initials: M
authors.lastname: Wu
authors.forename: Marylens
authors.initials: M
authors.lastname: Hernandez
authors.forename: Siming
authors.initials: S
authors.lastname: Shen
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Sabo
authors.forename: Dipti
authors.initials: D
authors.lastname: Kelkar
authors.forename: Ju
authors.initials: J
authors.lastname: Wang
authors.forename: Robert
authors.initials: R
authors.lastname: O'Leary
authors.forename: Greg R
authors.initials: GR
authors.lastname: Phillips
authors.forename: Holly S
authors.initials: HS
authors.lastname: Cate
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casaccia
mesh_terms: D000107:Acetylation; D000818:Animals; D000831:Animals, Newborn; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D020868:Gene Silencing; D053823:Hedgehog Proteins / Q000502:physiology*; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009836:Oligodendroglia / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D059467:Transcriptome / Q000235:genetics*
chemical_list: C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D053823:Hedgehog Proteins; D006657:Histones; C546888:Shh protein, rat; C515890:Hdac1 protein, rat; C533426:Hdac2 protein, rat; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2