PT  - JOURNAL ARTICLE
AU  - Muzhou Wu
AU  - Marylens Hernandez
AU  - Siming Shen
AU  - Jennifer K. Sabo
AU  - Dipti Kelkar
AU  - Ju Wang
AU  - Robert O'Leary
AU  - Greg R. Phillips
AU  - Holly S. Cate
AU  - Patrizia Casaccia
TI  - Differential Modulation of the Oligodendrocyte Transcriptome by Sonic Hedgehog and Bone Morphogenetic Protein 4 via Opposing Effects on Histone Acetylation
AID  - 10.1523/JNEUROSCI.4876-11.2012
DP  - 2012 May 09
TA  - The Journal of Neuroscience
PG  - 6651--6664
VI  - 32
IP  - 19
4099  - http://www.jneurosci.org/content/32/19/6651.short
4100  - http://www.jneurosci.org/content/32/19/6651.full
SO  - J. Neurosci.2012 May 09; 32
AB  - 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.