Mini Review
Roles of protein arginine methyltransferase 1 (PRMT1) in brain development and disease

https://doi.org/10.1016/j.bbagen.2020.129776Get rights and content

Highlights

  • PRMT1 catalyzes asymmetric dimethylation of arginine residues of proteins.

  • PRMT1 in neural stem cells is essential for early brain development.

  • Arginine methylation by PRMT1 and 5 are indispensable for myelination.

  • Methylation reduces phase separation of neurodegeneration-causative factors.

  • Methyl-arginine-specific antibodies and chemical tools accelerate PRMT study.

Abstract

Background

Protein arginine methyltransferase 1 (PRMT1), a major type I arginine methyltransferase in mammals, methylates histone and non-histone proteins to regulate various cellular functions such as transcription, DNA damage response, and signal transduction.

Scope of review

This review summarizes previous and recent studies on PRMT1 functions in major cell types of the central nervous system. We also discuss the potential involvement of PRMT1 in neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia. Also, we raise key questions that must be addressed in the future to more precisely understand the roles of PRMT1.

Major conclusions

Recent studies revealed that PRMT1 is essential for the development of neurons, astrocytes, and oligodendrocytes, although further investigation using cell type-specific PRMT1-deficient animals is required. In addition, the relevance of PRMT1 in neurodegenerative diseases will continue to be a hot topic.

General significance

PRMT1 is important for neural development and neurodegenerative diseases.

Introduction

Protein arginine methylation, a posttranslational modification recognized to be as important as phosphorylation or ubiquitination, is catalyzed by nine members of the protein arginine methyltransferase family (PRMT1–9) (Fig. 1). PRMTs are classified into type I, II, and III, depending on the modes of methylation (Fig. 1). All PRMTs catalyze mono-methylation of guanidino nitrogen atoms of arginine residues by using S-adenosylmethionine (SAM) as a methyl donor. However, only type I and II PRMTs further catalyze dimethylation of the mono-methylated arginine. The difference between type I and II is that type I PRMTs (PRMT1, 2, 3, 6, 8, and CARM1) form an asymmetric dimethyl arginine (ADMA), while type II PRMTs (PRMT5 and 9) form a symmetric dimethyl arginine (SDMA). Among type I PRMTs, PRMT1 is responsible for the biosynthesis of 85% of ADMA in mammals [1]. In contrast, type III PRMT (PRMT7) is only known for its monomethylation activity due to its unique structural features.

Protein arginine methylation has been implicated in many cellular processes such as transcription, signal transduction, cellular survival, DNA damage response, RNA processing, and transport or inflammatory responses [2,3]. The effects of arginine methylation on protein functions vary depending on the target proteins; therefore, arginine methylation does not serve as a simple switch for a certain functional change. Substrate specificity varies among PRMTs, and some members (PRMT1, 3, and 6) frequently target glycine-arginine-rich motifs on proteins. Regarding PRMT1, which is the main focus of this review, dozens of substrates (histone and non-histone proteins) have so far been identified. As the predominant type I PRMT, general roles of PRMT1 have been uncovered in conventional cultured cells. However, the in vivo physiological and pathological importance of PRMT1 in the central nervous system (CNS) remains largely unexplored.

Systemic knockout of PRMT1 results in early embryonic lethality [by embryonic day (E) 7.5], suggesting that PRMT1 is essential for embryonic development [4]. Although the reason for early death has not been uncovered, it suggests that PRMT1 is required for some postimplantation events. A growing number of studies from our and other research groups have identified tissue-specific functions of PRMT1 [5,6]. For example, PRMT1 is essential for embryonic vascular development [5] and normal heart function [6].

Although PRMT1 exhibits ubiquitous distribution throughout the body, its expression is first observed in the developing CNS and then spreads to all the major brain areas of the adult CNS [4]. Most of the PRMT family members, including PRMT1, 2, 3, 5, 7, 8 and CARM1, were confirmed to be expressed in the mouse brain by Western blot and/or immunohistochemistry [[7], [8], [9], [10], [11], [12]], and special attentions have been paid to hippocampal expression of PRMT3, 7 and 8. Notably, PRMT8 is a brain-specific member of type I PRMTs, and its expression increases after birth peaking at postnatal day(P) 21 in the hippocampus [12]. Compared to other PRMTs, expression of PRMT1 is seen at earlier stages in development, which implies its importance in stem cell biology and development. Brain cell RNA-seq studies reveled Prmt1 expression in all major CNS cell types, including neurons, astrocytes, oligodendrocytes, and microglia, with little difference in expression levels among these cell types [13]. Recent reports have revealed the significance of PRMT1 in neural cells, particularly in proliferation, differentiation, and development. Furthermore, several reports suggest the involvement of PRMT1 in various CNS diseases, including neurodegenerative disorders, brain tumors and multiple sclerosis. These findings suggest that PRMT1 critically regulates development and physiological functions of the brain.

This minireview highlights the roles of PRMT1 in development and regulation of the mammalian CNS, focusing on each neural cell type (Fig. 2). In addition, roles of PRMT1 in disease contexts are discussed.

Section snippets

PRMT1 in neural stem cells

Systemic knockout of Prmt1 in murine embryos was made by inserting βgeo into the second intron of the murine Prmt1 gene [4]. X-Gal-stained Prmt1-positive cells first appeared in the neural plate of heterozygotes at E7.5, and the signal got stronger as it developed into the neural tube and the brain at E8.5–E9.5 [4], implying that PRMT1 is important for early neural development.

Based on early seminal studies, PRMT1 is recognized as an important epigenetic regulator, as it methylates histone H4

PRMT1 in astrocytes, oligodendrocytes, and microglia

As described in the previous section, Honda et al. revealed that PRMT1 knockdown in cultured NSCs suppressed GFAP expression, leading to inhibition of astrocyte differentiation [9]. Interestingly, our recent work demonstrated increases in GFAP-positive astrocytes and IBA-1-positive microglia in cortices following PRMT1 knockout in NSCs in vivo [19]. We also found that purified astrocytes from CKO embryos expressed similar level of GFAP with astrocytes from wildtype embryos, suggesting that

PRMT1 in neurons

An earlier study by Cimato et al. demonstrated that total type I arginine-methylated protein levels are increased by nerve-growth factor (NGF) treatment on PC12 cells and this modification is essential for NGF-induced neurite outgrowth [23]. These studies first implicated that arginine methylation by type I PRMTs is important for neurite outgrowth. Similarly, Prmt1 knockdown in a neuroblastoma cell line, Neuro2a, reportedly results in a low number of neurite-bearing cells under

PRMT1 in neurodegenerative diseases

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes motor neuron dysfunction, resulting in muscle weakness. One of the disease-causative mutations for this fatal disease was identified in fused in sarcoma (FUS) protein, which belongs to the FET (FUS/EWS/TAF15) family of RNA binding proteins. In addition, FUS is mutated in rare cases of frontotemporal dementia (FTD), a major neurodegenerative disease [31]. Recent reports suggest that loss of PRMT1 is associated with

PRMT1 in other CNS diseases

A number of studies have focused on PRMT1 in cancer development, as reviewed elsewhere [39], but its involvement in CNS tumors has not been well studied so far. Medulloblastoma, a tumor observed in the cerebellum, is the most common type of brain tumor in childhood. In general, PRMT1 leads to apoptosis by methylation of BCL-2 antagonist of cell death (BAD) protein [40]. A recent report indicated that this PRMT1-BAD axis could suppress tumor development by increasing tumor apoptosis and PRMT1

Future perspectives

We here overviewed the physiological and pathological roles of PRMT1 in the CNS (Fig. 2), but there remain many open questions. First, what are the key substrates of PRMT1 regulating CNS development and functions? To address this question, highly sensitive and specific methods are required to enrich methylated substrates in the CNS. To this end, a set of antibodies targeting ADMA, SDMA, and MMA were generated using synthetic methylated peptides with arginine-glycine-rich motifs, and were

Author contributions

MH wrote the original manuscript, and MH, AF, TN, and YK revised the manuscript. All authors approved submission of the manuscript.

Declaration of Competing Interest

The authors declare that they have no conflicts of interest with regard to the contents of this article.

Acknowledgements

This work was partially supported by JSPS KAKENHI Grant-in-Aid for Research Activity Start-Up (17H06730) to MH, JSPS KAKENHI Grant-in-Aid for Young Scientists (20K15913) to MH, Grant-in-Aid for Scientific Research (A) (17H01519) to AF, JSPS Leading Initiative for Excellent Young Researchers (LEADER) to YK, the Gifu University Yoshizaki Research Support Fund (YRSF) to MH, Inamori Foundation Research Grants to MH, and The Mitsubishi Foundation to AF. We thank Edanz Group (//en-author-services.edanzgroup.com/ac

References (48)

  • M. Hashimoto et al.

    Region-specific upregulation of HNK-1 glycan in the PRMT1-deficient brain

    Biochim. Biophys. Acta (BBA).

    (2020)
  • M. Kato et al.

    Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels

    Cell.

    (2012)
  • A. Guo et al.

    Immunoaffinity enrichment and mass spectrometry analysis of protein methylation

    Mol. Cell. Proteomics

    (2014)
  • E. Guccione et al.

    The regulation, functions and clinical relevance of arginine methylation

    Nat. Rev. Mol. Cell Biol.

    (2019)
  • M.R. Pawlak et al.

    Arginine N-methyltransferase 1 is required for early postimplantation mouse development, but cells deficient in the enzyme are viable

    Mol. Cell. Biol.

    (2000)
  • T. Ishimaru et al.

    Angiodysplasia in embryo lacking protein arginine methyltransferase 1 in vascular endothelial cells

    J. Biol. Chem.

    (2017)
  • M. Honda et al.

    PRMT 1 regulates astrocytic differentiation of embryonic neural stem/precursor cells

    J. Neurochem.

    (2017)
  • W. Hou et al.

    Arginine methylation by PRMT2 controls the functions of the actin nucleator Cobl

    Dev. Cell

    (2018)
  • S. Lee et al.

    Methylation determines the extracellular calcium sensitivity of the leak channel NALCN in hippocampal dentate granule cells

    Exp. Mol. Med.

    (2019)
  • Y. Zhang et al.

    An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex

    J. Neurosci.

    (2014)
  • H. Wang et al.

    Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor

    Science.

    (2001)
  • Q. Zhao et al.

    PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing

    Nat. Struct. Mol. Biol.

    (2009)
  • A. Chittka

    Dynamic distribution of histone H4 arginine 3 methylation marks in the developing murine cortex

    PLoS One

    (2010)
  • M. Bezzi et al.

    Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery

    Genes Dev.

    (2013)
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