Alternative titles; symbols
HGNC Approved Gene Symbol: CARM1
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38) : 19:10,871,553-10,923,075 (from NCBI)
Protein arginine N-methyltransferases, such as CARM1, catalyze the transfer of a methyl group from S-adenosyl-L-methionine to the side chain nitrogens of arginine residues within proteins to form methylated arginine derivatives and S-adenosyl-L-homocysteine. Protein arginine methylation has been implicated in signal transduction, metabolism of nascent pre-RNA, and transcriptional activation (Frankel et al., 2002).
Members of the p160 family of proteins, which includes SRC1 (NCOA1; 602691) and GRIP1 (NCOA2; 601993), mediate transcriptional activation by nuclear hormone receptors. The AD2 activation domain, found in the C-terminal region of p160 proteins, plays an important role in p160 coactivator function. Using a yeast 2-hybrid system to screen a mouse 17 day-embryo cDNA library, Chen et al. (1999) isolated a cDNA clone encoding a 608-amino acid protein that bound to the C-terminal amino acids of GRIP1. The central portion of the coding region had extensive homology to a family of proteins with arginine-specific protein methyltransferase activity. The protein, coactivator-associated arginine methyltransferase-1 (CARM1), has a 3.8-kb mRNA that is widely but not evenly expressed in adult mouse tissues.
Ohkura et al. (2005) identified 4 alternatively-spliced rat Carm1 cDNAs, Carm1-v1 through Carm1-v4. The deduced proteins have between 573 and 608 amino acids. All contain the arginine methyltransferase domain and Grip1-binding domain, but they differ in their C-terminal domains. RT-PCR detected tissue-specific expression of the 4 transcripts.
By database analysis, Frankel et al. (2002) identified human PRMT4, which encodes a 608-amino acid protein. The catalytic core region of PRMT4 shares 29 to 36% amino acid identity with those of other PRMTs.
Because CARM1 is homologous to protein arginine methyltransferases, Chen et al. (1999) tested it for methyltransferase activity. Protein arginine methyltransferases transfer a methyl group from S-adenosylmethionine to the guanidino group nitrogen atoms in arginine residues of specific proteins. In vitro protein substrates for these enzymes include histones (see 142711) and proteins involved in RNA metabolism such as hnRNPA1 (164017), fibrillarin (134795), and nucleolin (164035). CARM1 preferentially methylated histone H3, either in a bulk histone preparation or in individually purified form. CARM1 coactivator function was specific for AD2 and correlated with its ability to bind GRIP1. CARM1 enhanced GRIP1 coactivator function for nuclear hormone receptors. The presence of both protein methyltransferase and transcriptional coactivator activities in CARM1 suggested that methylation of histones or other proteins, or both, may play a role in transcriptional regulation. CARM1 cDNA with the mutation in the putative S-adenosylmethionine-binding domain substantially reduced both methyltransferase and coactivator activities. In addition to GRIP1, CARM1 was also able to interact with other members of the p160 family of coactivators, including SRC1. Thus, coactivator-mediated methylation of proteins in the transcription machinery may contribute to transcriptional regulation.
Xu et al. (2001) described a molecular switch based on the controlled methylation of nucleosomes and the transcriptional cofactors, CBP (CREBBP; 600140)/p300 (EP300; 602700). These proteins share a methylation site localized to an arginine residue that is essential for stabilizing the structure of the KIX domain, which mediates CREB (CREB1; 123810) recruitment. Methylation of KIX by CARM1 blocks CREB activation by disabling the interaction between KIX and the kinase-inducible domain of CREB. Methylation analysis indicated that CARM1 methylates H3 acetylated nucleosomes in core histones and also, preferentially, p300. Xu et al. (2001) concluded that CARM1 functions as a corepressor in the cAMP signaling pathway via its methyltransferase activity while acting as a coactivator for nuclear hormones. CARM1 thus has chromatin and nonchromatin substrates. On the basis of in vitro and in vivo analyses, they proposed that histone methylation plays a key role in hormone-induced gene activation and that cofactor methylation is a regulatory mechanism in hormone signaling. Xu et al. (2001) suggested that their findings support the methylation 'code' hypothesis of Jenuwein and Allis (2001).
Using systems reconstituted with recombinant chromatin templates and coactivators, An et al. (2004) demonstrated the involvement of PRMT1 (602950) and CARM1 in p53 (191170) function; both independent and ordered cooperative functions of p300, PRMT1, and CARM1; and mechanisms involving direct interactions with p53 and obligatory modifications of corresponding histone substrates. Chromatin immunoprecipitation analyses confirmed the ordered accumulation of these (and other) coactivators and cognate histone modifications on a p53-responsive gene, GADD45 (126335), following ectopic p53 expression and/or ultraviolet irradiation.
HuR (ELAVL1; 603466) is an RNA-binding protein that stabilizes mRNAs carrying AU-rich instability elements (AREs). Li et al. (2002) found that mammalian Carm1 associated with HuR and activated HuR via methylation in vitro and in vivo. HuR methylation increased in cells that overexpressed Carm1, and lipopolysaccharide stimulation of mouse macrophages caused increased methylation of endogenous HuR, leading to the stabilization of TNF-alpha (TNF; 191160) mRNA.
Chen et al. (2002) demonstrated that Carm1 and Grip1 cooperatively stimulated the activity of Mef2c (600662) in mouse mesenchymal stem cells and found that there was direct interaction among Mef2c, Grip1, and Carm1. Chromatin immunoprecipitation assays demonstrated the in vivo recruitment of Mef2 and Carm1 to the endogenous muscle creatine kinase (CKM; 123310) promoter in a differentiation-dependent manner. Furthermore, Carm1 was expressed in somites during mouse embryogenesis and in the nuclei of muscle cells. Treatment of myogenic cells with a methylation inhibitor or antisense Carm1 did not affect expression of Myod (see MYOD1; 159970), but it inhibited differentiation and abrogated the expression of key transcription factors myogenin (MYOG; 159980) and Mef2 that initiate the differentiation cascade.
Ohkura et al. (2005) showed that rat Carm1-v3 associated with SNRPC (603522) and affected 5-prime splice site selection during pre-mRNA splicing. Carm1-v3, but not the other isoforms, stimulated a shift to the distal 5-prime splice site of the pre-mRNA when the adenoviral E1A minigene was used as a reporter and enhanced exons skipping in the CD44 (107269) reporter. The v3-specific C terminal and regions conserved among the isoforms were required for this activity, but arginine methyltransferase activity was not. Among the 4 rat Carm1 isoforms, Carm1-v3 showed the highest activity as a cofactor for reporter activity from an estrogen-responsive element (ERE), both in the presence and absence of Grip1. Carm1-v1, but not Carm1-v3, showed reduced coactivator activity from the ERE when arginine methyltransferase activity was lost. All Carm1 variants showed comparable methylation of histone H3.
Using mouse and human cells, El Messaoudi et al. (2006) showed that CARM1 is a regulator of cyclin E1 (CCNE1; 123837) and DHFR (126060) mRNA expression.
By screening for methylated proteins in a mouse B-cell line, followed by in vitro and in vivo methylation assays, Cheng et al. (2007) identified Smb (SNRPB; 182282), Sap49 (SF3B4; 605593), U1c (SNRPC), and Ca150 (TCERG1; 605409) as splicing factors targeted by Carm1. Human CARM1 altered the patterns of exon choice in splicing a CD44 reporter minigene and endogenous CD44 in mouse and human cell lines.
The carboxy-terminal domain of RNA polymerase II (see 180660) in mammals undergoes extensive posttranslational modification, which is essential for transcriptional initiation and elongation. Sims et al. (2011) showed that the carboxy-terminal domain of RNA polymerase II is methylated at a single arginine (R1810) by CARM1. Although methylation at R1810 is present on the hyperphosphorylated form of RNA polymerase II in vivo, ser2 or ser5 phosphorylation inhibits CARM1 activity toward this site in vitro, suggesting that methylation occurs before transcription initiation. Mutation of R1810 results in the misexpression of a variety of small nuclear RNAs and small nucleolar RNAs, an effect that is also observed in Carm1 -/- mouse embryo fibroblasts. Sims et al. (2011) concluded that carboxy-terminal domain methylation facilitates the expression of select RNAs, perhaps serving to discriminate the RNA polymerase II-associated machinery recruited to distinct gene types.
Sanchez et al. (2013) found that Carm1 mRNA coimmunoprecipitated with Smn1 (600354) in polyribosomes isolated from mouse motoneuron-derived MN-1 cells. In vitro-translated human SMN1 repressed translation of Carm1 mRNA, but had no effect on global mRNA translation, in MN-1 cells.
Shin et al. (2016) identified CARM1 as a crucial component of autophagy in mammals. Notably, CARM1 stability is regulated by the SKP2 (601436)-containing SCF (SKP1-cullin1-F-box protein) E3 ubiquitin ligase complex in the nucleus, but not in the cytoplasm, under nutrient-rich conditions. Furthermore, Shin et al. (2016) showed that nutrient starvation results in AMPK-dependent phosphorylation of FOXO3A (602681) in the nucleus, which in turn transcriptionally represses SKP2. This repression leads to increased levels of CARM1 protein and subsequent increases in histone H3 arg17 dimethylation. Genomewide analyses revealed that CARM1 exerts transcriptional coactivator function on autophagy-related and lysosomal genes through transcription factor EB (TFEB; 600744). Shin et al. (2016) concluded that CARM1-dependent histone arginine methylation is a crucial nuclear event in autophagy, and that they identified a novel signaling axis of AMPK-SKP2-CARM1 in the regulation of autophagy induction after nutrient starvation.
Frankel et al. (2002) determined that the CARM1 gene contains 16 exons.
By genomic sequence analysis, Frankel et al. (2002) mapped the CARM1 gene to chromosome 19. Wolf (2009) reported that the CARM1 gene maps to chromosome 19p13.2.
Yadav et al. (2003) showed that mouse embryos with a targeted disruption of the Carm1 gene were small in size and died perinatally. The methylation of 2 Carm1 substrates, Pabp1 (604679) and the transcriptional cofactor p300 (602303), was abolished in knockout embryos and cells. Furthermore, estrogen-responsive gene expression was aberrant in Carm1 -/- fibroblasts and embryos.
An, W., Kim, J., Roeder, R. G. Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. Cell 117: 735-748, 2004. [PubMed: 15186775] [Full Text: https://doi.org/10.1016/j.cell.2004.05.009]
Chen, D., Ma, H., Hong, H., Koh, S. S., Huang, S.-M., Schurter, B. T., Aswad, D. W., Stallcup, M. R. Regulation of transcription by a protein methyltransferase. Science 284: 2174-2177, 1999. [PubMed: 10381882] [Full Text: https://doi.org/10.1126/science.284.5423.2174]
Chen, S. L., Loffler, K. A., Chen, D., Stallcup, M. R., Muscat, G. E. O. The coactivator-associated arginine methyltransferase is necessary for muscle differentiation: CARM1 coactivates myocyte enhancer factor-2. J. Biol. Chem. 277: 4324-4333, 2002. [PubMed: 11713257] [Full Text: https://doi.org/10.1074/jbc.M109835200]
Cheng, D., Cote, J., Shaaban, S., Bedford, M. T. The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Molec. Cell 25: 71-83, 2007. [PubMed: 17218272] [Full Text: https://doi.org/10.1016/j.molcel.2006.11.019]
El Messaoudi, S. E., Fabbrizio, E., Rodriguez, C., Chuchana, P., Fauquier, L., Cheng, D., Theillet, C., Vandel, L., Bedford, M. T., Sardet, C. Coactivator-associated arginine methyltransferase 1 (CARM1) is a positive regulator of the cyclin E1 gene. Proc. Nat. Acad. Sci. 103: 13351-13356, 2006. [PubMed: 16938873] [Full Text: https://doi.org/10.1073/pnas.0605692103]
Frankel, A., Yadav, N., Lee, J., Branscombe, T. L., Clarke, S., Bedford, M. T. The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity. J. Biol. Chem. 277: 3537-3543, 2002. [PubMed: 11724789] [Full Text: https://doi.org/10.1074/jbc.M108786200]
Jenuwein, T., Allis, C. D. Translating the histone code. Science 293: 1074-1080, 2001. [PubMed: 11498575] [Full Text: https://doi.org/10.1126/science.1063127]
Li, H., Park, S., Kilburn, B., Jelinek, M. A., Henschen-Edman, A., Aswad, D. W., Stallcup, M. R., Laird-Offringa, I. A. Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. J. Biol. Chem. 277: 44623-44630, 2002. [PubMed: 12237300] [Full Text: https://doi.org/10.1074/jbc.M206187200]
Ohkura, N., Takahashi, M., Yaguchi, H., Nagamura, Y., Tsukada, T. Coactivator-associated arginine methyltransferase 1, CARM1, affects pre-mRNA splicing in an isoform-specific manner. J. Biol. Chem. 280: 28927-28935, 2005. [PubMed: 15944154] [Full Text: https://doi.org/10.1074/jbc.M502173200]
Sanchez, G., Dury, A. Y., Murray, L. M., Biondi, O., Tadesse, H., El Fatimy, R., Kothary, R., Charbonnier, F., Khandjian, E. W., Cote, J. A novel function for the survival motoneuron protein as a translational regulator. Hum. Molec. Genet. 22: 668-684, 2013. [PubMed: 23136128] [Full Text: https://doi.org/10.1093/hmg/dds474]
Shin, H.-J., Kim, H., Oh, S., Lee, J.-G., Kee, M., Ko, H.-J., Kweon, M.-N., Won, K.-J., Baek, S. H. AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature 534: 553-557, 2016. [PubMed: 27309807] [Full Text: https://doi.org/10.1038/nature18014]
Sims, R. J., III, Rojas, L. A., Beck, D., Bonasio, R., Schuller, R., Drury, W. J., III, Eick, D., Reinberg, D. The C-terminal domain of RNA polymerase II is modified by site-specific methylation. Science 332: 99-103, 2011. [PubMed: 21454787] [Full Text: https://doi.org/10.1126/science.1202663]
Wolf, S. S. The protein arginine methyltransferase family: an update about function, new perspectives and the physiological role in humans. Cell. Molec. Life Sci. 66: 2109-2121, 2009. [PubMed: 19300908] [Full Text: https://doi.org/10.1007/s00018-009-0010-x]
Xu, W., Chen, H., Du, K., Asahara, H., Tini, M., Emerson, B. M., Montminy, M., Evans, R. M. A transcriptional switch mediated by cofactor methylation. Science 294: 2507-2511, 2001. [PubMed: 11701890] [Full Text: https://doi.org/10.1126/science.1065961]
Yadav, N., Lee, J., Kim, J., Shen, J., Hu, M. C.-T., Aldaz, C. M., Bedford, M. T. Specific protein methylation defects and gene expression perturbations in coactivator-associated arginine methyltransferase 1-deficient mice. Proc. Nat. Acad. Sci. 100: 6464-6468, 2003. [PubMed: 12756295] [Full Text: https://doi.org/10.1073/pnas.1232272100]