Histone deacetylase fate switch

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Science Signaling  16 Feb 2016:
Vol. 9, Issue 415, pp. ec33
DOI: 10.1126/scisignal.aaf4571

Oligodendrocyte precursor cells usually differentiate into oligodendrocytes, which produce the myelin sheaths that insulate neurons, but these precursors can also differentiate into astrocytes under certain conditions. Whereas the transcription factor Olig2 promotes oligodendrogenesis, Janus kinase (Jak)–Stat signaling promotes astrogenesis. Zhang et al. found that the histone deacetylase Hdac3, which was abundant in oligodendrocyte precursor cells from neonatal rats, determined which fate these cells adopted. Exposing these cells to an Hdac3-specific inhibitor, but not inhibitors that target other HDACs, reduced Olig2 expression. Mice lacking Hdac3 specifically in oligodendrocyte precursor cells exhibited locomotor phenotypes indicative of myelination defects, as well as reduced myelination, reduced expression of myelin-specific genes, and reduced numbers of Olig2-positive cells throughout the central nervous system. The mutant mice also had more astrocytes than controls and no increase in cell death in the brain, suggesting that cells that would normally have given rise to oligodendrocytes instead differentiated into astrocytes. Indeed, Hdac3–/– oligodendrocyte precursors expressed astrocyte-specific genes rather than oligodendrocyte-specific genes, and in vivo lineage tracing experiments confirmed that Hdac3 deficiency caused oligodendrocyte precursor cells to differentiate into astrocytes. Chromatin immunoprecipitation analysis showed that Hdac3 bound to the enhancers of both oligodendrocyte- and astrocyte-specific genes, but it colocalized with the histone acetyltransferase (HAT) p300 only at the enhancers of oligodendrocyte-specific genes. This implies that Hdac3 represses the expression of astrocyte-specific genes, but cooperates with p300 to promote the expression of oligodendrocyte-specific genes. Acetylation of Stat transcription factors promotes their ability to dimerize and stimulate target gene expression. Acetylated Stat3 was more abundant in Hdac3–/– oligodendrocytes than control oligodendrocytes, and treating wild-type oligodendrocyte precursors with an Hdac3 inhibitor in culture increased Stat3 acetylation and promoted differentiation of these cells into astrocytes. Coimmunoprecipitation assays and experiments with a fluorescent reporter that is activated by Stat3 and p300 in 293T cells demonstrated that Hdac3 competed with Stat3 for binding to p300, indicating that Hdac3 can prevent formation of the Stat3-p300 transcriptional activator complex. These results imply that not only does Hdac3 promote Olig2 expression and cooperate with p300 to promote the expression of oligodendrocyte-specific genes, it also deacetylates Stat3 to prevent expression of astrocyte-specific genes.

L. Zhang, X. He, L. Liu, M. Jiang, C. Zhao, H. Wang, D. He, T. Zheng X. Zhou, A. Hassan, Z. Ma, M. Xin, Z. Sun, M. A. Lazar, S. A. Goldman,
E. N. Olson, Q. R. Lu. Hdac3 interaction with p300 histone acetyltransferase regulates the oligodendrocyte and astrocyte lineage fate switch, Dev. Cell 36, 316–330 (2016). [PubMed]

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