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.