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Histone methyltransferase enhancer of zeste homolog 2 regulates Schwann cell differentiation
Author(s) -
Heinen André,
Tzekova Nevena,
Graffmann Nina,
Torres Klintsy Julieta,
Uhrberg Markus,
Hartung HansPeter,
Küry Patrick
Publication year - 2012
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22388
Subject(s) - biology , ezh2 , schwann cell , microbiology and biotechnology , histone methyltransferase , cellular differentiation , epigenetics , enhancer , myelin , chromatin immunoprecipitation , gene expression , genetics , neuroscience , gene , promoter , central nervous system
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. © 2012 Wiley Periodicals, Inc.