Type II Arginine Methyltransferase PRMT5 Regulates Gene Expression of Inhibitors of Differentiation/DNA Binding Id2 and Id4 during Glial Cell Differentiation

Jinghan Huang,Gillian Vogel,Zhenbao Yu,Guillermina Almazan,Stéphane Richard

doi:10.1074/jbc.m111.277046

Jinghan Huang, Gillian Vogel + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m111.277046

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Abstract

PRMT5 is a type II protein arginine methyltranferase that catalyzes monomethylation and symmetric dimethylation of arginine residues. PRMT5 is functionally involved in a variety of biological processes including embryo development and circadian clock regulation. However, the role of PRMT5 in oligodendrocyte differentiation and central nervous system myelination is unknown. Here we show that PRMT5 expression gradually increases throughout postnatal brain development, coinciding with the period of active myelination. PRMT5 expression was observed in neurons, astrocytes, and oligodendrocytes. siRNA-mediated depletion of PRMT5 in mouse primary oligodendrocyte progenitor cells abrogated oligodendrocyte differentiation. In addition, the PRMT5-depleted oligodendrocyte progenitor and C6 glioma cells expressed high levels of the inhibitors of differentiation/DNA binding, Id2 and Id4, known repressors of glial cell differentiation. We observed that CpG-rich islands within the Id2 and Id4 genes were bound by PRMT5 and were hypomethylated in PRMT5-deficient cells, suggesting that PRMT5 plays a role in gene silencing during glial cell differentiation. Our findings define a role of PRMT5 in glial cell differentiation and link PRMT5 to epigenetic changes during oligodendrocyte differentiation.

Highlights

Elevated PRMT5 Expression in Brain Coincides with CNS Myelination—To identify a role for protein arginine methylation during CNS myelination, we examined the expression of the major Protein arginine methyltransferases (PRMTs) in brain lysates in postnatal mice
The brain expression of PRMT5, a type II enzyme that generates symmetric DMA, gradually increased after P11 and peaked in adult mice (Fig. 1). These findings show that elevated PRMT5 expression coincides with CNS myelination, and we focused our studies on PRMT5
We demonstrate that PRMT5 is required for oligodendrocyte differentiation, supported by several observations

Summary

Introduction

PRMT5 Regulates Oligodendrocyte Differentiation histone proteins interferes with gene expression. We uncovered that PRMT5 expression level in brain gradually increases during active myelination, and knockdown of PRMT5 expression leads to impaired oligodendrocyte differentiation. At day 2 postdifferentiation, knockdown of QKI prevented oligodendrocyte differentiation, as indicated by an increase (p Ͻ 0.0001) of A2B5-positive cells, an early oligodendrocyte progenitor marker (Fig. 4, B and C).

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