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. 2022 Jun 3;10(6):2383–2392. doi: 10.1016/j.gendis.2022.05.021

Coactivator-associated arginine methyltransferase 1: A versatile player in cell differentiation and development

Zhongrui Ma a,b,1, Xinxing Lyu a,c,1, Ning Qin c, Haoyu Liu c, Mengrui Zhang c, Yongchao Lai a, Bo Dong d, Peiyuan Lu a,b,c,∗
PMCID: PMC10404874  PMID: 37554200

Abstract

Protein arginine methylation is a common post-translational modification involved in the regulation of various cellular functions. Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein arginine methyltransferase that asymmetrically dimethylates histone H3 and non-histone proteins to regulate gene transcription. CARM1 has been found to play important roles in cell differentiation and development, cell cycle progression, autophagy, metabolism, pre-mRNA splicing and transportation, and DNA replication. In this review, we describe the molecular characteristics of CARM1 and summarize its roles in the regulation of cell differentiation and development in mammals.

Keywords: Arginine methylation, CARM1, Cell differentiation, Development, Epigenetic regulation

Introduction

Post-translational modifications (PTMs) of proteins play significant roles in signal transduction and epigenetic regulation of gene expression. The nitrogen atoms of an arginine residue within a protein can be covalently linked to methyl groups, a process termed protein arginine methylation. Protein arginine methylation is catalyzed by the nine members of the protein arginine methyltransferase (PRMT) family.1 PRMTs catalyze the transfer of a methyl group from S-adenosyl-l-methionine to the guanidino nitrogen atoms of an arginine residue within a protein, resulting in the formation of methylarginine and S-adenosyl-l-homocysteine.2 There are three forms of methylarginine identified in eukaryotes: monomethylarginine (MMA), asymmetric dimethylarginine (aDMA), and symmetric dimethylarginine (sDMA)3, 4, 5, 6 (Fig. 1). Protein arginine methylation is a key PTM that is very common in mammals.7 It is involved in regulating diverse important biological processes, including transcriptional regulation, pre-mRNA processing, signal transduction, DNA damage response, mRNA translation, and cell fate decision.3, 4, 5, 6

Figure 1.

Fig. 1

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Types of methylation on arginine residues. PRMTs can transfer a methyl group from S-adenosyl-l-methionine to the guanidino nitrogen atoms of an arginine (Arg) residue and result in the formation of a monomethylarginine (MMA), asymmetric dimethylarginine (aDMA), or symmetric dimethylarginine (sDMA) residue in a protein.

Coactivator-associated arginine methyltransferase 1 (CARM1, also known as PRMT4) is a PRMT that was discovered as a transcriptional coactivator of nuclear receptors (NRs) by Stallcup and colleagues in 1999.8 CARM1 can asymmetrically dimethylate R17, R26, and R42 of histone H3 to generate the H3R17me2a, H3R26me2a, and H3R42me2a marks, which are associated with activation of transcription.4,5,9 It also regulates transcription by catalyzing arginine methylation of non-histone proteins, leading to both enhanced and repressed transcriptional activities of various transcription factors. For example, methylation of CBP at R742 by CARM1 enhances GRIP-1- and steroid hormone-induced gene activation,10 whereas methylation of CBP at R600 in the KIX domain by CARM1 represses the transcriptional activity of CREB.11 This dual function of CARM1 in transcriptional regulation implicates that it could play a role in multiple cellular functions. Indeed, CARM1 is found to be involved in cell cycle progression,12 autophagy,13, 14, 15, 16 metabolism,17, 18, 19, 20 DNA damage response,21 pre-mRNA splicing,22, 23, 24 and DNA replication.25 Recently, more and more studies have shown that CARM1 is also a critical regulator of cell differentiation and development. In this review, we will first describe the structure of CARM1 and regulation of its activity by PTMs, then we will discuss its roles in mammalian cell differentiation and embryonic development.

Structure of CARM1 and regulation of its activities by PTMs

The human, mouse, and rat CARM1 genes all contain 16 exons. Five alternatively spliced variants of Carm1 have been identified in rats.22,26 Variant 1 is the full-length version of Carm1, which is composed of all the 16 exons. The isoform encoded by variant 1 is termed CARM1FL. Variant 2 retains intron 15 in addition to the 16 exons. Variant 3 contains introns 14, but lacks exons 15 and 16. Variant 4 excludes exon 15 and encodes the isoform termed CARM1ΔE15. Variant 5 retains a part of intron 15 in addition to the 16 exons.22,26 Only two alternatively spliced variants of CARM1 have been identified in human and mice. They encode CARM1FL and CARM1ΔE15 respectively.27,28 CARM1ΔE15 is the dominant form in most human tissues, whereas CARM1FL seems to be the major isoform only in brain, heart, skeletal muscle, and testis.27 The specific functions of all these CARM1 isoforms are still not well understood and need to be clarified in the future.

CARM1 is composed of an N-terminal domain, a C-terminal domain, and a central PRMT catalytic core29, 30, 31 (Fig. 2). The N-terminal domain has a pleckstrin homology (PH) domain, which is a scaffold frequently found to mediate protein–protein interactions in a large variety of biological processes.30 It is involved in substrate recognition and therefore indispensable for substrate methylation.32 The C-terminal domain possesses a strong autonomous transcriptional activation domain (TAD), which is necessary for CARM1 to act as a transcriptional coactivator of NRs.29 The central PRMT catalytic core is composed of a Rossmann fold and a beta-barrel. It is essential for substrate binding and methyltransferase activity of CARM1.29,31 The catalytic core contains the five conserved signature PRMT motifs: motif I (VLD/EVGXGXG), motif post-I (V/IXG/AXD/E), motif II (F/I/VDI/L/K), motif III (LR/KXXG), and THW loop (THWXQ).1,3,33,34 There is also a dimerization arm in the central catalytic core. CARM1 forms dimers through this dimerization arm in vivo,29, 30, 31 and just like other PRMTs,35 dimerization seems to be essential for its methyltransferase activity.36 A CARM1 mutant that fails to form dimers shows reduced methyltransferase activity in in vitro methylation assays.36 In addition, the central catalytic core has a nuclear localization sequence (NLS), which is necessary for the nuclear localization of CARM1.20

Figure 2.

Fig. 2

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Schematic diagram of the structure and PTMs of CARM1. CARM1 is composed of an N-terminal domain, a C-terminal domain, and a central PRMT catalytic core. The N-terminal domain has a pleckstrin homology (PH) domain and is involved in substrate recognition. The C-terminal domain possesses a transcriptional activation domain (TAD) and is necessary for CARM1 to act as a transcriptional coactivator. The central PRMT catalytic core is composed of a Rossmann fold and a beta-barrel. It contains the five conserved signature PRMT motifs. There is also a dimerization arm (DA) and a nuclear localization sequence (NLS) in the central catalytic core. The PTMs of CARM1 include phosphorylation, ubiquitination, methylation, and O-GlcNAcylation. The enzymes that catalyze these PTMs are also shown in this schematic diagram. Phosphorylation of S572 of CARM1ΔE15 is labelled to S595 of CARM1FL that is corresponding to it. O-GlcNAcylation of S598, T601, and T603 is not displayed due to space limitation. I, motif I; p-I, motif post-I; II, motif II; III, motif III; THW, THW loop; SCF E3, SKP2-containing SCF E3 ubiquitin ligase complex; OGT, O-GlcNAc transferase.

CARM1 catalyzes arginine methylation of proteins, but itself is also subjected to multiple PTMs, including phosphorylation,28,36, 37, 38, 39, 40 O-GlcNAcylation,41, 42, 43 ubiquitination,13,14,44 and methylation24,27(Fig. 2). These modifications regulate the methyltransferase activity, dimerization, cellular localization, substrate specificity, and stability of CARM1 (Table 1). PTMs of CARM1 play important roles in various biological processes. S217 (in this article, all the amino acid residues of CARM1 are numbered according to mouse and rat CARM1FL unless specifically indicated) phosphorylation and S229 phosphorylation of CARM1 both occur during mitosis, indicating that these two PTMs may be involved in cell cycle regulation.36,37 Decreased O-GlcNAcylation level of CARM1 in M phase is required for correct chromosomal segregation during mitosis.42 K471 ubiquitination of CARM1 by the SKP2-containing SKP1-cullin 1-F-box protein (SCF) E3 ubiquitin ligase complex plays an important role in the regulation of autophagy.13,14 R551 dimethylation of CARM1 via an automethylation mechanism is essential for it to act as a transcriptional coactivator of ERα and regulate pre-mRNA splicing as well.24,27

Table 1.

PTMs of CARM1.

PTM type PTM site Enzyme Effects on CARM1 References
Phosphorylation T132 GSK-3β Protects it from ubiquitin-mediated proteasomal degradation in lung epithelial cells 40
S217 unknown Abolishes its methyltransferase activity by inhibiting SAM binding. Impairs its nuclear localization 37
S229 PKC Abolishes its methyltransferase activity by inhibiting SAM binding. Interferes with its dimerization 36,39
S448 PKA Is necessary and sufficient for it to bind directly to the unliganded hormone-binding domain of ERα 38
S572 of CARM1ΔE15 p38γ/MAPK12 Disrupts its nuclear localization 28
O-GlcNAcylation S595, S598, T601, and T603 O-GlcNAc transferase Alters its substrate specificity 41, 42, 43
Ubiquitination K471 SKP2-containing SCF E3 ubiquitin ligase complex Controls its nuclear protein level 13,14
Methylation R551 CARM1 Is essential for it to act as a transcriptional coactivator of ERα and regulate pre-mRNA splicing 24,27
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Roles of CARM1 in cell differentiation and development

CARM1 plays critical roles in cell differentiation and embryonic development. Unlike PRMT1 or PRMT5,45,46 Carm1 knockout does not result in complete embryonic lethality in mice, but the neonates die shortly after birth.47 Carm1−/− embryos are smaller than their wild-type littermates. They also display retarded endochondral ossification and reduced chondrocyte proliferation,48 impaired hematopoiesis and decreased thymopoiesis,49,50 deficient adipocyte differentiation,51 and abnormal differentiation of pulmonary epithelial cells,47,52 suggesting that CARM1 is essential for these embryonic developmental events. Recently, CARM1 is also found to regulate early embryonic development via biasing cell fate in pre-implantation mouse embryos.53, 54, 55, 56, 57 In addition, CARM1 is required for skeletal muscle differentiation58,59 and spermiogenesis60 in adult mice. Here, we will describe in detail the roles of CARM1 in early embryonic development, T cells development and hematopoiesis, lung morphogenesis, skeletal muscle differentiation as well as spermiogenesis. The substrates, methylated arginine residues, and effects of arginine methylation during these processes are outlined in Table 2.

Table 2.

Roles of CARM1 in cell differentiation and development.

Process Substrate Methylated arginine residues Effects of arginine methylation References
Early embryonic development Histone H3 R17, R26 Transcriptional activation 53,54,55,56,57,63,65
BAF155 Not determined Decreased stability of the SWI/SNF complex 66
T cells development and Hematopoiesis Not determined – Proper cellularity and survival of hematopoietic progenitor cells 49,50
Lung morphogenesis Not determined – Proper expression of Aqp1, Aqp5, Gadd45g, Scn3b, and Nkd1 52
Skeletal muscle differentiation Pax7 R10, R13, R22, R37 Activation of Myf5 expression 59
Histone H3 R17 Activation of the expression of late myogenic genes and myogenic microRNAs 75,76
Spermiogenesis p300 R2142 Impaired formation of p300-ACT-CREMτ complex 60
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Early embryonic development

CARM1 regulates cell fate determination during early embryonic development. After fertilization, the first cell fate bias occurs in the two-cell stage.61 This bifurcates the totipotent zygote into the inner cell mass (ICM), which contributes to the fetus, and the trophectoderm (TE), which contributes to the placenta. CARM1 is required for this first cell lineage segregation.56,57 It interacts with LincGET, an endogenous retrovirus-associate lncRNA, through its TAD in the two-to four-cell mouse embryos.56 This interaction localizes CARM1 to paraspeckles,57 which are membrane-free dynamic structures working as open systems as their components exchange with freely diffusing molecules in the nucleoplasm.62 LincGET/CARM1 complexes are asymmetrically distributed between the blastomeres of the two-to four-cell mouse embryos, which results in asymmetric levels of H3R26me2a as well as the expression of the ICM-specific genes Sox2, Nanog, and Sox21. Thus, the blastomere containing more LincGET/CARM1 complexes is biased toward an ICM cell fate.56

CARM1 also contributes to cell fate determination in the four-cell mouse embryos through a similar mechanism. CARM1 is heterogeneously distributed between the blastomeres of the four-cell mouse embryos,53,63 which is regulated by microRNA (miRNA) miR-181a.63 This leads to different levels of H3R26me2a as well as heterogeneous expression of the ICM-specific genes Sox2, Nanog, and Sox21 in the blastomeres of the four-cell mouse embryos.53,54 Because Sox21 inhibits the expression of the TE master gene Cdx2, Cdx2 is also heterogeneously expressed in the blastomeres of the four-cell mouse embryos.54 Thus, this heterogeneous gene expression profile biases cell fate decisions at the four-cell stage. Very interestingly, CARM1-mediated H3R26 dimethylation leads to long-lived DNA binding of Sox2 but not Oct4 in the four-cell mouse embryos,55 although Oct4 collaboratively activates Sox21 transcription with Sox2.64 H3R26me2a-induced long-lived DNA binding of Oct4 also occurs at the eight-cell stage.55

In addition to H3R26 dimethylation, it seems that CARM1-mediated H3R17 dimethylation is also involved in the regulation of early mouse embryonic development.53,65 Moreover, CARM1 regulates cell fate determination in the pre-implantation mouse embryos via methylating the SWI/SNF chromatin remodeling complex component BAF155, a major SWI/SNF complex subunit that regulates its assembly. The SWI/SNF complex represses the expression of the pluripotency-related gene Nanog in the TE lineage. CARM1-mediated arginine methylation of BAF155 decreases the stability of the SWI/SNF complex and thus increases the expression of Nanog in the pluripotent epiblast lineage.66

In summary, CARM1 ensures proper lineage allocation via methylation of histone H3 and other factors at their arginine residues to regulate the gene expression program for proper cell fate determination during early embryonic development (Fig. 3).

Figure 3.

Fig. 3

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Regulation of early embryonic development by CARM1. CARM1 is heterogeneously distributed between the blastomeres of the two-cell and four-cell mouse embryos, which leads to different levels of H3R26me2a and H3R17me2a as well as heterogeneous expression of the ICM-specific genes Sox2, Nanog, and Sox21 and the TE master gene Cdx2 in these cells. This heterogeneous gene expression profile biases cell fate decisions at the two-cell and four-cell stage.

T cells development and hematopoiesis

CARM1 is required for hematopoiesis and T cell differentiation during embryonic development.49,50 Compared with their wild type littermates, Carm−/− mouse embryos exhibit a significant reduction in thymocyte cellularity and a decreased proportion of double negative thymocytes due to a partial arrest in the development of the early thymocyte progenitors.49 Reduced thymopoiesis in Carm−/− mouse embryos is due to a defect in the fetal hematopoietic compartment rather than in the thymic stroma.50 CARM1 functions cell-intrinsically to regulate the activity and cellularity of hematopoietic progenitor cells in the fetal liver and bone marrow. CARM1 deficiency remarkably reduces cellularity of hematopoietic progenitors in the embryonic bone marrow, and Carm1−/− fetal liver cells show a deficit in the ability to contribute to hematopoiesis.50 Moreover, CARM1 is required for the survival of hematopoietic progenitors, particularly at the earliest stages of T cell differentiation.50 Taken together, CARM1 is a key regulator of hematopoiesis and T cell development that affects multiple lineages at different stages of differentiation during embryonic development. However, CARM1 is not indispensable for hematopoiesis in adult mice. Conditional knockout of Carm1 in adult mice has little effect on hematopoiesis.67 Furthermore, CARM1 plays essential roles in myeloid leukemogenesis. Loss of CARM1 strongly impairs both the initiation and maintenance of acute myeloid leukemia (AML) by inhibiting cell-cycle progression, promoting myeloid differentiation, and inducing apoptosis in AML cells, suggesting that CARM1 may be an effective therapeutic target for AML.67 However, the exact mechanisms by which CARM1 regulates hematopoiesis and T cell differentiation as well as myeloid leukemogenesis are not clear and need to be clarified. It will be necessary to identify the substrates of CARM1 and the involved genes during these processes to answer these questions.

Lung morphogenesis

The lungs of the Carm1−/− neonates failed to inflate with air after birth, and their alveolar air spaces were smaller compared with their wild-type littermates,47 suggesting that CARM1 is required for normal lung morphogenesis.

Development of the lung is tightly regulated by a cascade of signaling pathways and various transcription factors.68,69 At the late stage of embryogenesis, bipotent alveolar progenitor cells of the distal lung differentiate into pulmonary epithelial alveolar type I (AT1) and alveolar type II (AT2) cells.70 AT1 cells are large squamous cells that coordinate the air exchange of capillaries in the distal lung. AT2 cells are smaller cuboidal cells located in the alveolar sacs, which produce surfactant to reduce their surface tension in order that they can be filled with air. CARM1 plays an important role in regulating the proliferation and differentiation of pulmonary epithelial cells.52 Hyperproliferation of AT2 cells occurs in the lung of Carm1−/− mice, but differentiation of AT1 cells is blocked in the absence of CARM1, resulting in smaller alveolar air spaces in the distal lung.52 CARM1 controls proliferation and differentiation of pulmonary epithelial cells through regulating the expression of the genes crucial for cell cycle regulation and AT1 differentiation, including Aqp1, Aqp5, Gadd45g, Scn3b, and Nkd1.52 Further investigations are needed to identify the substrates of CARM1 in alveolar progenitor cells to elucidate the molecular mechanisms by which CARM1 regulates proper expression of these genes during lung morphogenesis.

Skeletal muscle differentiation

CARM1 is an important regulator of asymmetric satellite stem cell divisions in skeletal muscle.59 Satellite stem cells are a small subset of satellite cells that are located beneath the basal lamina surrounding myofibers. They are essential for the growth and regeneration of skeletal muscle.71,72 Satellite stem cells can expand their number through symmetric divisions and give rise to committed myogenic progenitors through asymmetric divisions.73, 74, 75 During asymmetric satellite stem cell divisions, CARM1 regulates satellite stem cell entry into the myogenic program via epigenetic activation of the myogenic determination factor gene Myf5, a target gene of the transcription factor Pax7, in the committed satellite myogenic cells.59 CARM1 specifically methylates the multiple arginine residues in the N-terminus of the transcription factor Pax7. Methylated Pax7 directly binds the C-terminal cleavage forms of the trithorax proteins MLL1/2 and recruits the MLL histone H3K4 methyltransferase complex to the enhancers and proximal promoter of Myf5, resulting in increased H3K4me3 levels at these loci and de novo activation of Myf5 transcription in the committed satellite myogenic cells following asymmetric satellite stem cell divisions.59 Thus, methylation of Pax7 by CARM1 acts as a switch that activates the expression of Myf5 during the satellite stem cell asymmetric divisions and entry into the myogenic program (Fig. 4).

Figure 4.

Fig. 4

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Regulation of asymmetric satellite stem cell divisions by CARM1. During asymmetric satellite stem cell divisions, CARM1 specifically methylates the multiple arginine residues in the N-terminus of the transcription factor Pax7 in the committed satellite myogenic cells. Methylated Pax7 directly binds the C-terminal cleavage forms of the trithorax proteins MLL1/2 and recruits the MLL histone H3K4 methyltransferase (HMT) complex to the enhancers and proximal promoter of the myogenic determination factor gene Myf5, resulting in increased H3K4me3 levels at these loci and de novo activation of Myf5 transcription in the committed satellite myogenic cells. These committed satellite myogenic cells then differentiate into myoblasts.

CARM1 is also essential for the differentiation of skeletal muscle cells. It functions as a transcriptional coactivator of the transcription factors of the myocyte enhancer factor-2 (MEF2) family to activate myogenic gene expression.58 Moreover, CARM1 is also required for the expression of late myogenic genes 76and myogenic microRNAs.77 It dimethylates H3R17 of the upstream regulatory regions of late myogenic genes and myogenic microRNAs to facilitate the binding of myogenin and the Brg1 ATPase of the SWI/SNF complex to these loci to activate their expression.76,77

Spermiogenesis

Although CARM1 is not required for spermatocyte development, it is essential for the late stage of haploid spermatid development.60 CARM1 is highly expressed in the mouse testis, and its moves from cytoplasmic to nuclear during the spermatocyte to spermatid transition, suggesting an important role of CARM1 in the late stages of sperm development. Loss of CARM1 leads to a significant drop in sperm count as well as an accumulation of immature germ cells and aberrant sperms in the cauda epididymis. The anomalies in sperm cell morphology and structure include abnormal head formations, headless sperms, and sperms with a bent midpiece. Moreover, Loss of CARM1 causes a dramatic decrease in the motility of sperms.60

CARM1 regulates the late stages of spermiogenesis via repressing the transcriptional activity of the testis-specific transcription factor cAMP response element modulator tau (CREMτ),60 which is a master regulator of the early stage of haploid spermatid development.78 During the late stages of sperm development, CARM1 dimethylates R2142 in the GRIP1 binding domain (GBD) domain of p300，which is a coactivator of CREMτ. This attenuates the interaction of p300 with activator of CREMτ in the testis (ACT), the mediator of the interaction between CREMτ and p300, resulting in an inhibition of the p300-ACT-CREMτ-mediated transcription program in the haploid spermatids.60

Conclusions and perspectives

CARM1 is a PRMT that functions as an important transcriptional regulator. It regulates transcription through asymmetric dimethylation of histone H3 as well as non-histone proteins. Moreover, CARM1 can both enhance and repress the transcriptional activities of various transcription factors. This dual functionality of CARM1 in transcriptional regulation makes it a critical regulator of cell differentiation and embryonic development. It not only regulates early embryonic development via biasing cell fate in the two-cell and four-cell mouse embryos, but also play essential roles in endochondral ossification and chondrocyte proliferation, hematopoiesis and thymopoiesis, adipocyte differentiation, lung morphogenesis, skeletal myogenesis, spermiogenesis, etc. The enzymatic activity seems to be required for these functions of CARM1, because the enzyme-dead Carm1 knockin mice have similar defects to those seen in their knockout counterparts.79 Moreover, the two isoforms, CARM1FL and CARM1ΔE15, could play distinctive roles in cell differentiation and embryonic development due to their differential tissue distributions.27 It will be of great importance to explore this area more comprehensively. In addition, more efforts are needed to identify new CARM1 substrates to better characterize its functions in cell differentiation and embryonic development, and it is necessary to clarify how CARM1-mediated arginine methylation is recognized and how the signals are transduced especially when the substrates are non-histone proteins.

Because of its significant roles in cell differentiation and embryonic development, CARM1 is involved in a couple of human disorders, including cancer,3,4,6,9 muscular atrophy,28,80, 81, 82 diabetic nephropathy,44,83,84 and senescence.85, 86, 87 Understanding the functions of CARM1 in cell differentiation and embryonic development may shed light on the pathogenesis and therapies of these diseases. Indeed, some recently developed specific and potent CARM1 small-molecule inhibitors have been tested to treat a subset of cancers.67,88, 89, 90, 91 Hopefully they could become approved drugs for cancer treatment in the future.

Conflict of interests

The authors declare no conflict of interests.

Funding

This work was supported by Funding for Top-notch Personnel from Shandong First Medical University and Taishan Scholars Program (No. ts 2019097).

Acknowledgements

We thank Dr. Mike Powell at Emory University for proofreading the manuscript and Home for Researcher (www.home-for-researchers.com) for optimizing the figures.

Footnotes

Peer review under responsibility of Chongqing Medical University.

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