title: Histone methyltransferase enhancer of zeste homolog 2 regulates Schwann cell differentiation.
abstract: Epigenetic control is crucial for the differentiation of a variety of cells including oligodendrocytes, the myelinating glial cells of the central nervous system. However, studies about the implication of epigenetic factors in peripheral nervous system maturation are just emerging. Here, we demonstrate for the first time the impact of a histone methyltransferase, encoded by the enhancer of zeste homolog 2 (EZH2) gene, on Schwann cell differentiation. In sciatic nerves, EZH2 expression was found in Schwann cells and to peak perinatally. Suppression of EZH2 expression in cultured primary rat Schwann cells reduced the length of cell processes. These morphological changes were accompanied by widespread alterations in the gene expression pattern, including downregulation of myelin genes and induction of p57kip2, which we have recently identified as an intrinsic inhibitory regulator of Schwann cell maturation. In addition, we show that EZH2 suppression in dorsal root ganglion cocultures interferes with in vitro myelination. Chromatin immunoprecipitation analysis revealed binding of EZH2 at the p57kip2 promoter and reduction of histone H3K27 trimethylation upon gene suppression. EZH2 suppression-dependent effects on morphology and myelin genes could be reversed by concomitant suppression of p57kip2, indicating that p57kip2 is a downstream effector of EZH2. Furthermore, we describe Hes5 as transcriptional repressor of myelin genes in Schwann cells, which was induced upon EZH2 suppression and downregulated in p57kip2-suppressed Schwann cells. Therefore, we have identified a molecular link between histone methylation and control of Schwann cell differentiation and demonstrate that this epigenetic mechanism is crucial for glial differentiation to proceed.
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
authors: André
authors: A
authors: Heinen
authors: Nevena
authors: N
authors: Tzekova
authors: Nina
authors: N
authors: Graffmann
authors: Klintsy Julieta
authors: KJ
authors: Torres
authors: Markus
authors: M
authors: Uhrberg
authors: Hans-Peter
authors: HP
authors: Hartung
authors: Patrick
authors: P
authors: Küry
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D048430:Cell Shape; D002478:Cells, Cultured; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism*; D012584:Sciatic Nerve / Q000166:cytology / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; D000071221:Enhancer of Zeste Homolog 2 Protein; D006657:Histones; D063151:Polycomb Repressive Complex 2; D012097:Repressor Proteins; C489686:Hes5 protein, rat; C578253:EZH2 protein, rat