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

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. Protein arginine methyltransferases (PRMTs)3 transfer methyl groups from S-adenosylmethionine to the nitrogen atoms of arginine, a positively charged amino acid that mediates hydrogen bonding and amino aromatic interactions (1). Arginine can be monomethylated or dimethylated (DMA). If two methyl groups are both placed on one of the terminal nitrogen atoms of the guanidino group, the derivative is an asymmetric DMA. Symmetric DMA is where one methyl group is located on each of the two nitrogens. There are currently nine mammalian PRMTs that are grouped as type I and type II enzymes (1, 2). Type I enzymes form monomethylated arginine and asymmetric DMA and include PRMT1, PRMT3, CARM1, PRMT6, and PRMT8. Type II enzymes, including PRMT5, PRMT7, and PRMT9, catalyze the production of monomethylated arginine and symmetric DMA. The enzyme activity of PRMT2 is not yet identified.Symmetrical arginine dimethylation occurs less frequently than asymmetrical dimethylation, and among the type II enzymes, PRMT5 has been the most characterized. It is functionally involved in a broad spectrum of biological processes, but most importantly in early embryo development and later cellular differentiation as well as the circadian clock (3-6). Accumulating evidence reveals that PRMT5 recurrently exerts its biological functions through transcriptional repression of a large group of genes involved in these processes. PRMT5 associates with the cyclin E1 promoter and represses cyclin E1 transcription, leading to inhibition of cell proliferation (7). PRMT5 associates with BRG1-based SWItch/Sucrose NonFermentable (hSWI/SNF) chromatin remodeling complexes and promotes transcriptional repression of the Myc target gene cad (8). BRG1-and hBRM-associated PRMT5 also repress...

Severe Hypomyelination and Developmental Defects Are Caused in Mice Lacking Protein Arginine Methyltransferase 1 (PRMT1) in the Central Nervous System

“…In the present study, we found that PRMT1 plays a critical role in oligodendrocyte lineage progression. A previous study has shown that PRMT5 knockdown in C6 rat glioma cells and primary rat OPCs led to repressed maturation of oligodendrocyte, indicating that PRMT5 is important for oligodendrocyte differentiation (12). These studies suggest that both PRMT1 and PRMT5 positively regulate oligodendrocyte development.…”

“…Interestingly, the distribution pattern of PRMT1 in mouse embryo has shown high expression in neural tube during embryonic stage (9). After birth, PRMT1 is still strongly expressed in the brain during the perinatal stage (12). It should be noted that PRMT5, the most characterized member of type II PRMTs that catalyze the monomethylation and symmetric dimethylation of proteins, also shows substantial expression in the brain (12).…”

“…After birth, PRMT1 is still strongly expressed in the brain during the perinatal stage (12). It should be noted that PRMT5, the most characterized member of type II PRMTs that catalyze the monomethylation and symmetric dimethylation of proteins, also shows substantial expression in the brain (12). Specific deletion of PRMT5 in CNS results in postnatal lethality with extensive apoptosis of NSCs (13).…”

Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth

“…As the major PRMT catalyzing the SDMA modification of proteins, PRMT5 is involved in tumorigenesis via histone methylation and transcriptional gene silencing (39,40). Some nonhistone proteins are also directly methylated by PRMT5, resulting in tumor progression (41)(42)(43).…”

The QKI-5 and QKI-6 RNA Binding Proteins Regulate the Expression of MicroRNA 7 in Glial Cells

“…Glial cells such as oligodendrocytes are known to be regulated at multiple levels by epigenetics changes, including histone modifications and miRNAs (43,44). The expression of Ͼ37 miRNAs is regulated during oligodendrocyte differentiation (45).…”