| 2000 |
CARM1 functions as a transcriptional coactivator for nuclear receptors (e.g., estrogen receptor) by binding to the AD2 domain of p160 coactivators (e.g., GRIP1), and synergizes with p300 (which binds AD1) to enhance receptor-dependent transcription; both binding interactions are required for their respective coactivator functions. |
Transient transfection reporter assays, deletion mutant analysis of GRIP1 AD1/AD2 domains |
The Journal of biological chemistry |
High |
11010967
|
| 2001 |
CARM1 methylates histone H3 at Arg17 and Arg26 in a hormone-dependent manner at specific gene promoters (e.g., MMTV), and this methyltransferase activity is required for its coactivator function in steroid hormone receptor-dependent transcription. |
Chromatin immunoprecipitation, immunofluorescence on stably integrated MMTV promoter arrays, methyltransferase-dead mutant rescue experiments |
Current biology : CB |
High |
11747826
|
| 2001 |
CARM1 is required for skeletal myogenesis by coactivating MEF2C through direct protein-protein interactions with MEF2C and GRIP-1; CARM1 is recruited to the endogenous muscle creatine kinase promoter in a differentiation-dependent manner. |
Co-immunoprecipitation, chromatin immunoprecipitation, antisense/methylation inhibitor loss-of-function, reporter assays |
The Journal of biological chemistry |
High |
11713257
|
| 2002 |
CARM1 specifically methylates the RNA-binding protein HuR at Arg217 (in the hinge region between RRM2 and RRM3); this methylation is induced by lipopolysaccharide stimulation of macrophages and correlates with HuR-mediated stabilization of TNFα mRNA. |
In vitro methylation assays, arginine-to-lysine mutant mapping, radioactive peptide sequencing, anti-methylated HuR antibodies, in vivo methylation in LPS-stimulated macrophages |
The Journal of biological chemistry |
High |
12237300
|
| 2002 |
Crosstalk exists between CBP/p300-mediated acetylation and CARM1-mediated arginine methylation on histone H3: acetylation at H3K18 and K23 (but not K14) tethers CARM1 to the H3 tail and enhances its methyltransferase activity at R17; at the estrogen-responsive pS2 promoter, CBP binding and H3K18 acetylation precede CARM1 recruitment and H3R17 methylation. |
Chromatin immunoprecipitation time-course following estrogen stimulation, in vitro binding/methylation assays with acetylated H3 peptides, CBP acetyltransferase-dead mutant |
Current biology : CB |
High |
12498683
|
| 2004 |
PRMT1, p300/CBP, and CARM1 act in an ordered, cooperative manner during p53-dependent transcriptional activation: they interact directly with p53 and modify histones at the GADD45 gene in a defined sequence; reconstituted chromatin templates demonstrate these are obligatory histone modifications. |
Reconstitution with recombinant chromatin templates and purified (co)activators, chromatin immunoprecipitation following p53 induction/UV irradiation |
Cell |
High |
15186775
|
| 2005 |
A specific CARM1 isoform (CARM1-v3), generated by intron retention and lacking the C-terminal domain, associates with U1C (U1 snRNP protein) and promotes alternative 5' splice site selection and exon skipping, in an isoform-specific manner requiring the v3-specific C-terminal sequences. |
Isoform-specific expression, minigene splicing reporter assays (E1A, CD44), co-immunoprecipitation with U1C, deletion mutant analysis |
The Journal of biological chemistry |
Medium |
15944154
|
| 2006 |
CARM1 acts as a transcriptional coactivator for E2F1/DP1-driven expression of CCNE1 (Cyclin E1) and DHFR; it is recruited to these promoters via ACTR (p160 family), deposits H3R17 and H3R26 methylation at the transcriptional start site, and is required for proper CCNE1 expression kinetics following growth stimulation. |
Chromatin immunoprecipitation, CARM1-deficient cells, reporter gene assays |
Proceedings of the National Academy of Sciences of the United States of America |
High |
16938873
|
| 2007 |
CARM1 methylates splicing factors CA150, SAP49, SmB, and U1C; methylation of CA150 by CARM1 regulates its interaction with the Tudor domain of SMN in a methylation-dependent manner; CARM1 promotes exon skipping in an enzyme-dependent manner at CD44 and exogenous splicing reporters. |
Small-pool substrate screening, in vitro methylation assays, co-immunoprecipitation, splicing reporter assays (CD44 and exogenous minigene), enzyme-dead CARM1 mutant |
Molecular cell |
High |
17218272
|
| 2009 |
CARM1 enzymatic activity is required for all its known in vivo functions: enzyme-dead knock-in mice phenocopy CARM1 knockout mice with respect to embryo lethality timing, T cell development, adipocyte differentiation, and transcriptional coactivator activity. |
Enzyme-dead knock-in mouse model (compared to knockout), T cell development assays, adipocyte differentiation assays, transcriptional reporter assays |
The Journal of biological chemistry |
High |
19897492
|
| 2009 |
CARM1 methyltransferase activity is regulated by phosphorylation at Ser217 by an unidentified kinase: phosphorylation disrupts a hydrogen bond between Ser217 and Tyr154 that locks SAM in the binding cavity, thereby abolishing methyltransferase activity; phospho-Ser217 also promotes cytoplasmic relocalization of CARM1 during mitosis. |
Structural analysis of CARM1 crystal structures, in vitro methyltransferase assays with phosphomimetic mutants, cell fractionation/immunofluorescence during mitosis |
The Journal of biological chemistry |
High |
19843527
|
| 2009 |
CARM1 regulates endochondral ossification by methylating Sox9 at its HMG domain; methylation of Sox9 disrupts its interaction with β-catenin, thereby regulating Cyclin D1 expression and chondrocyte cell cycle progression. |
CARM1 null and transgenic mice, in vitro and in vivo methylation assays, co-immunoprecipitation of Sox9/β-catenin |
BMC developmental biology |
High |
19725955
|
| 2009 |
CARM1 is required for embryonic stem cell self-renewal and pluripotency by methylating H3R17 and H3R26 at pluripotency gene promoters (Oct4, Sox2, Nanog); CARM1 depletion downregulates these pluripotency genes and causes differentiation. |
CARM1 knockdown in ES cells, chromatin immunoprecipitation at Oct4/Sox2/Nanog promoters, CARM1 overexpression experiments |
Stem cells (Dayton, Ohio) |
High |
19544422
|
| 2010 |
CARM1 undergoes automethylation at Arg551 in its C-terminal domain (CTD); this automethylation does not affect enzymatic activity but is required for CARM1-activated transcription and pre-mRNA splicing, providing a mechanism linking transcription and splicing through the CTD. |
Top-down high-resolution mass spectrometry, in vitro and in vivo automethylation assays, Arg551Lys mutant functional analysis in transcription and splicing reporters |
Nucleic acids research |
High |
21138967
|
| 2010 |
PKA phosphorylates CARM1 at a single serine, which is necessary and sufficient for CARM1 to bind directly to the unliganded hormone-binding domain (HBD) of ERα, enabling cAMP/PKA-dependent, ligand-independent activation of ERα transcription. |
In vitro kinase assays, direct binding assays (GST pulldown), phosphomimetic mutants, reporter gene assays, ERα deletion mutant mapping |
Genes & development |
High |
20360387
|
| 2011 |
Crystal structures of CARM1 catalytic domain in complex with cofactors (SAH or sinefungin) and inhibitors reveal that inhibitors bind in the arginine-binding cavity at the N-/C-terminal domain interface; binding requires pre-formed cofactor SAH; key selectivity residues distinguish CARM1 from PRMT1 and PRMT3. |
X-ray crystallography, isothermal titration calorimetry |
The Biochemical journal |
High |
21410432
|
| 2012 |
CARM1 methylates multiple arginines in the N-terminus of Pax7; methylated Pax7 directly binds the C-terminal cleavage forms of MLL1/2 trithorax proteins, recruiting the ASH2L:MLL1/2:WDR5:RBBP5 H3K4 methyltransferase complex to Myf5 regulatory elements, thereby driving de novo Myf5 transcription during asymmetric satellite stem cell divisions. |
Co-immunoprecipitation of Pax7 with CARM1 and MLL1/2, in vitro methylation assays, chromatin immunoprecipitation, conditional Carm1 knockout in satellite cells |
Cell stem cell |
High |
22863532
|
| 2014 |
CARM1 methylates the SWI/SNF core subunit BAF155 at R1064; methylated BAF155 is directed to unique chromatin regions (e.g., c-Myc pathway gene loci) and regulates breast cancer cell migration and metastasis. |
Zinc-finger nuclease CARM1 knockout cell lines, mass spectrometry substrate identification, site-specific mutagenesis (R1064), chromatin immunoprecipitation, migration/metastasis assays |
Cancer cell |
High |
24434208
|
| 2015 |
CARM1 methylates p54nrb at its coiled-coil domain, reducing p54nrb binding to mRNAs containing inverted repeated Alu elements (IRAlus); CARM1 also transcriptionally suppresses NEAT1 lncRNA to reduce paraspeckle formation, together attenuating nuclear retention of IRAlu-containing mRNAs. |
CARM1 knockout/knockdown, RNA immunoprecipitation, in vitro methylation of p54nrb, paraspeckle imaging, mRNA nuclear/cytoplasmic fractionation |
Genes & development |
High |
25792598
|
| 2015 |
CARM1 methylates MED12 at R1862 and R1912; methylated MED12 suppresses p21/WAF1 transcription through a mechanism distinct from TGF-βR signaling, and methylation-deficient MED12 cells are resistant to chemotherapy drugs. |
In vitro methylation assays, site-specific mutagenesis, drug sensitivity assays, ChIP, CARM1/MED12 co-immunoprecipitation |
Science advances |
High |
26601288
|
| 2015 |
Crystal structures of human CARM1 with sinefungin cofactor and peptide substrates from histone H3 and PABP1 (both unmethylated and monomethylated arginine) reveal how the CARM1 binding site accommodates diverse peptide sequences while maintaining a core binding mode. |
X-ray crystallography of ternary complexes |
ACS chemical biology |
High |
26551522
|
| 2016 |
CARM1 protein stability is regulated in the nucleus (but not cytoplasm) by the SCF-SKP2 E3 ubiquitin ligase under nutrient-rich conditions; nutrient starvation activates AMPK-dependent phosphorylation of FOXO3a, which transcriptionally represses SKP2, leading to CARM1 accumulation, increased H3R17 dimethylation, and transcriptional coactivation of autophagy-related and lysosomal genes through TFEB. |
In vivo ubiquitination assays, AMPK inhibitor/activator experiments, FOXO3a phosphomimetic mutants, ChIP-seq (H3R17me2a), RNA-seq, co-immunoprecipitation of CARM1/TFEB |
Nature |
High |
27309807
|
| 2016 |
CARM1 methylates MDH1 at R248, inhibiting its enzymatic activity by disrupting MDH1 dimerization; this methylation negatively regulates glutamine metabolism and NADPH production in pancreatic cancer cells. |
In vitro methylation assays, MDH1 dimerization assays, site-specific mutagenesis (R248), metabolic flux measurements, CARM1 knockdown with rescue experiments |
Molecular cell |
High |
27840030
|
| 2017 |
Quantitative mass spectrometry globally profiled >130 CARM1 substrates in breast cancer cells; >90% of methylation sites were validated in vitro; bioinformatics revealed enrichment of proline-containing motifs; the N-terminus of CARM1 is critical for substrate recognition. |
Quantitative proteomics (SILAC), in vitro methylation validation, N-terminal deletion mutants for substrate recognition |
Nature communications |
High |
28537268
|
| 2017 |
CARM1 methylates PKM2 (but not PKM1) at specific arginine residue(s); methylated PKM2 interacts with and suppresses inositol-1,4,5-trisphosphate receptors (InsP3Rs), inhibiting calcium influx from ER to mitochondria and shifting metabolism from oxidative phosphorylation to aerobic glycolysis. |
In vitro methylation assays, co-immunoprecipitation of methylated PKM2 with InsP3Rs, calcium flux measurements, metabolic profiling, nanoparticle-delivered competitive peptide inhibition |
Nature cell biology |
High |
29058718
|
| 2018 |
CARM1 methylates GAPDH at R234, inhibiting GAPDH catalytic activity and suppressing glycolysis; glucose starvation increases CARM1 expression and R234 hypermethylation. |
In vitro methylation assays, site-specific mutagenesis (R234), GAPDH activity assays, glycolytic flux measurements, CARM1 KO/rescue experiments |
Cell reports |
High |
30232003
|
| 2018 |
CARM1 methylates MED12 at R1899 (major site); methylated MED12 is recognized by the Tudor domain-containing effector TDRD3; this methylation-dependent TDRD3 recruitment to ERα-specific enhancers is required for MED12 to interact with activating noncoding RNAs and for estrogen-regulated gene transcription. |
CARM1 substrate motif antibody immunoprecipitation + mass spectrometry, site-specific mutagenesis (R1899), co-immunoprecipitation of TDRD3 with methylated MED12, ChIP-seq |
Life science alliance |
High |
30456381
|
| 2018 |
CARM1 methylates p300 and this methylation negatively regulates the p300•ACT•CREMτ axis during spermiogenesis; high nuclear CARM1 impairs CREMτ-driven transcription during late stages of haploid germ cell development. |
Germline-specific conditional Carm1 knockout mice, RNA-seq, co-immunoprecipitation of ACT/CREMτ/p300 complex, in vitro methylation of p300 |
Nucleic acids research |
High |
29659998
|
| 2018 |
JMJD6 is required for MED12 to interact with CARM1; CARM1 methylates MED12 at multiple arginine sites, regulating its chromatin binding at ERα-bound active enhancers, and is required for ERα-induced transcriptional pause release. |
Co-immunoprecipitation (JMJD6-MED12-CARM1 complex), ChIP-seq, in vitro methylation assays, JMJD6 knockdown epistasis |
Molecular cell |
High |
29628309
|
| 2020 |
CARM1-mediated methylation of BAF155 (SWI/SNF subunit) drives a switch from SWI/SNF complex to EZH2 at the MAD2L2 promoter, silencing MAD2L2 expression and promoting homologous recombination; EZH2 inhibition restores MAD2L2 and sensitizes CARM1-high cancers to PARP inhibitors. |
ChIP at MAD2L2 promoter (BAF155, EZH2, SWI/SNF), methylated-BAF155 antibody, CARM1 KO/reconstitution, genetic epistasis with EZH2 inhibitor, xenograft models |
Cancer cell |
High |
32004442
|
| 2021 |
CARM1 associates with replication forks and slows fork speed independently of its methyltransferase activity; it interacts with PARP1 and stimulates PARP1 activity by enhancing its DNA binding, acting jointly with HPF1; this promotes fork reversal over translesion synthesis during replication stress. |
iPOND (isolation of proteins on nascent DNA), in vitro PARP1 activity assays with CARM1 and HPF1, siRNA knockdown epistasis (RECQ1, RAD18), single-molecule DNA fiber analysis, co-immunoprecipitation of CARM1-PARP1 |
Molecular cell |
High |
33412112
|
| 2021 |
CARM1 directly interacts with XBP1s and regulates XBP1s target gene expression during ER stress; CARM1-expressing ovarian cancer cells are selectively sensitive to IRE1α/XBP1s pathway inhibition. |
Co-immunoprecipitation of CARM1 and XBP1s, gene expression analysis, CARM1 KO cell lines, in vitro and xenograft models |
Nature communications |
Medium |
34493732
|
| 2014 |
PRMT4/CARM1 methylates retinoblastoma protein (pRb) at R775, R787, and R798 in vitro (R787 in vivo); arginine methylation of pRb facilitates its phosphorylation and disrupts the E2F-1/DP1-pRb complex, thereby reducing pRb's ability to repress E2F-1 transcriptional activation. |
In vitro methylation assays, site-specific mutagenesis (R775/787/798), methylmimetic mutant pRb (R3F), co-immunoprecipitation of pRb-E2F-1, Gal4-E2F-1 reporter assay |
Molecular and cellular biology |
High |
25348716
|
| 2015 |
CARM1 promotes nonsense-mediated mRNA decay (NMD) of PTC-containing mRNAs and associates with NMD factor UPF1, promoting UPF1 occupancy on PTC-containing transcripts; CARM1 upregulation in spinal muscular atrophy may exacerbate NMD of specific transcripts. |
NMD reporter assays, co-immunoprecipitation of CARM1 with UPF1, RNA immunoprecipitation, CARM1 knockdown with NMD target expression analysis |
Nucleic acids research |
Medium |
26656492
|
| 2017 |
H3K27 acetylation recruits the Super Elongation Complex (SEC); this further stimulates H3R26 methylation by CARM1, which then abrogates SEC recruitment, forming a negative feedback loop; inhibiting CARM1 methyltransferase activity reactivates HIV-1 transcription in latency models. |
Histone modification ChIP, SEC binding assays with acetylated vs. methylated H3 peptides, CARM1 inhibitor treatment in HIV latency cell models including primary CD4+ T cells |
Nucleic acids research |
Medium |
28637181
|
| 2013 |
CARM1 methylates HuR at R217, and this methylation enhances HuR's ability to regulate turnover of specific target mRNAs (cyclin A, cyclin B1, c-fos, SIRT1, p16); in replicative senescence, reduced CARM1 correlates with reduced HuR methylation and impaired mRNA stabilization function. |
CARM1 knockdown and R217K HuR mutant in HeLa cells, mRNA stability assays, RNA immunoprecipitation (p16 3'UTR binding), joint knockdown epistasis |
BMC molecular biology |
Medium |
23837869
|
| 2018 |
CARM1 methylates NFIB transcription factor; the effector molecule TRIM29 binds methylated NFIB; both CARM1 and the CARM1 methylation site on NFIB are critical for rapid onset of small cell lung cancer (SCLC) in a mouse model, and maintain similar open chromatin states in tumors. |
In vitro methylation assays, co-immunoprecipitation of TRIM29 with methylated NFIB, SCLC mouse model with CARM1 KO and methylation-site NFIB mutant, ATAC-seq |
Nature communications |
High |
36690626
|
| 2020 |
PRMT6 can also deposit the H3R17me2a mark in vitro, partially redundantly with CARM1; CARM1/PRMT6 double-knockout mouse embryonic fibroblasts lack H3R17me2a during mitosis and show increased DNA damage, providing in vivo evidence of functional redundancy. |
In vitro histone methyltransferase assay with PRMT6, double-KO mouse embryos, immunofluorescence for H3R17me2a during mitosis, DNA damage markers |
The Journal of biological chemistry |
High |
33008887
|
| 2024 |
CARM1 methylates DRP1 at R403 and R634 in the cytoplasm; methylated DRP1 interacts with mitochondrial fission factor (Mff) and self-assembles on the outer mitochondrial membrane to trigger mitochondrial fission, reducing oxygen consumption and increasing ROS; ROS-activated p38γ MAPK phosphorylates CARM1 at S595, promoting its translocation from nucleus to cytoplasm, establishing a positive feedback loop leading to cellular senescence. |
In vitro methylation assays (DRP1), co-immunoprecipitation of methylated DRP1 with Mff, live cell mitochondrial imaging, ROS measurements, p38γ kinase assays with CARM1 S595 mutant, CARM1/DRP1 knockdown phenotype analysis |
Redox biology |
High |
38838552 39265499
|
| 2013 |
PRMT4/CARM1 acts as a coactivator of c-Myb target gene expression in hematopoietic cells by interacting with chromatin remodeler Mi2α/Mi2β; this coactivation requires both CARM1 methyltransferase activity and Mi2 ATPase activity; knockdown of CARM1 or Mi2α/β reduces c-Myb target gene expression, cell growth, and causes deregulated differentiation. |
Co-immunoprecipitation of CARM1 with Mi2α/β, ChIP at c-Myb target genes, methyltransferase-dead CARM1 mutant, Mi2 ATPase-dead mutant, CARM1/Mi2 knockdown in erythroid cells |
PLoS genetics |
High |
23505388
|
| 2023 |
CARM1 methylates PPP1CA at R23; this methylation affects dephosphorylation of AKT-T450 and AMPK-T172, increases activities of phosphofructokinase-1 and PFKFB3, causing upregulation of glycolytic flux and promoting osteogenic differentiation while inhibiting osteoclastic differentiation. |
In vitro methylation assays, CARM1 CRISPR KO and lentiviral overexpression, transcriptomic and metabolomic profiling, AKT/AMPK phosphorylation assays, osteogenic/osteoclastic differentiation assays |
Clinical and translational medicine |
Medium |
37649137
|
| 2022 |
CARM1 methylates ACSL4 at R339; this methylation promotes RNF25 binding to ACSL4, leading to RNF25-mediated ubiquitylation and degradation of ACSL4, thereby suppressing ferroptosis; CARM1 inhibition increases ACSL4 levels and sensitizes cells to ferroptosis inducers. |
In vitro methylation assays, site-specific mutagenesis (R339), co-immunoprecipitation of RNF25 with methylated ACSL4, ubiquitylation assays, ferroptosis sensitivity assays in vitro and in vivo |
Advanced science |
High |
37946697
|
| 2022 |
PRMT4/CARM1 methylates Nrf2, restricting its nuclear translocation and suppressing GPX4 transcription, thereby promoting ferroptosis in doxorubicin-induced cardiomyopathy. |
Co-immunoprecipitation of PRMT4 with Nrf2, in vitro methylation assay, nuclear/cytoplasmic fractionation of Nrf2 with PRMT4 OE/KO, GPX4 reporter and protein expression, ferroptosis assays |
Cell death and differentiation |
High |
35383293
|
| 2023 |
PRMT4/CARM1 methylates PPARγ at Arg240, enhancing its interaction with the coactivator PRDM16, thereby promoting thermogenic gene expression and white adipose tissue browning. |
In vitro methylation assay, site-specific mutagenesis (R240), co-immunoprecipitation of PPARγ-PRDM16 with WT vs. R240 mutant, gene expression analysis, adipose-specific PRMT4 overexpression mouse model |
Diabetes |
High |
37216643
|
| 2021 |
CARM1 is normally targeted for proteasomal degradation by the SCFFBXO9 E3 ubiquitin ligase, which interacts with CARM1 via a phosphodegron and ubiquitinates CARM1 at K228; endotoxin reduces SCFFBXO9 levels, increasing CARM1 and causing caspase 3-mediated lung epithelial cell death. |
Co-immunoprecipitation of SCFFBXO9 with CARM1, in vitro ubiquitination assay at K228, PRMT4 KO in cellular and murine injury models, caspase 3 activity measurements |
Cell death & disease |
High |
34480022
|
| 2016 |
CARM1 stability in the nucleus is regulated by the SCF-SKP2 E3 ubiquitin ligase; under nutrient starvation, AMPK-dependent FOXO3a phosphorylation represses SKP2 transcription, preventing CARM1 ubiquitination and degradation in the nucleus (but not cytoplasm). |
Ubiquitination assays, nuclear/cytoplasmic fractionation, FOXO3a phosphomimetic mutants, SKP2 knockdown/overexpression, AMPK activation/inhibition |
Nature |
High |
27309807
|