Enzymatic Activity Is Required for the in Vivo Functions of CARM1

Kim, Daehoon; Lee, Jae-Ho; Cheng, Donghang; Li, Jia; Carter, Carla; Richie, Ellen R.; Bedford, Mark T.

doi:10.1074/jbc.m109.035865

Cited by 65 publications

(73 citation statements)

References 37 publications

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“…The methyltransferase activity of CARM1 is required for its ability to regulate transcription of pS2 (TFF1), a standard ERα target gene (5). Moreover, the enzyme-dead CARM1 knockin mice have defects similar to those seen in their knockout counterparts (6). These observations suggest that the enzymatic activity of CARM1 is indispensable for the majority of CARM1's in vivo functions.…”

mentioning

confidence: 55%

Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

2012

Proc. Natl. Acad. Sci. U.S.A.

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The histone coactivator-associated arginine methyltransferase 1 (CARM1) is a coactivator for a number of transcription factors, including nuclear receptors. Although CARM1 and its asymmetrically deposited dimethylation at histone H3 arginine 17 (H3R17me2a) are associated with transcription activation, the mechanism by which CARM1 activates transcription remains unclear. Using an unbiased biochemical approach, we discovered that the transcription elongation-associated PAF1 complex (PAF1c) directly interacts with H3R17me2a. PAF1c binds to histone H3 tails harboring dimethylation at R17 in CARM1-methylated histone octamers. Knockdown of either PAF1c subunits or CARM1 affected transcription of CARM1-regulated, estrogen-responsive genes. Furthermore, either CARM1 knockdown or CARM1 enzyme-deficient mutant knockin resulted in decreased H3R17me2a accompanied by the reduction of PAF1c occupancy at the proximal promoter estrogen-responsive elements. In contrast, PAF1c knockdown elicited no effects on H3R17me2a but reduced the H3K4me3 level at estrogen-responsive elements. These observations suggest that, apart from PAF1c's established roles in directing histone modifications, PAF1c acts as an arginine methyl histone effector that is recruited to promoters and activates a subset of genes, including targets of estrogen signaling.estrogen receptor-α | histone arginine methylation | PRMT

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confidence: 55%

Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Although the basal levels of p21 and Gadd45 mRNA varied in the three MEF cell lines, it is inappropriate to compare basal levels between these cell lines, since each cell line was derived from a different mouse. CARM1 +/+ and CARM1(KI) MEF cells express similar levels of CARM1 protein (Kim et al 2010). It is interesting to note that DNA damage-induced expression of both p21 and Gadd45 requires BRCA1 (MacLachlan et al 2002;Aylon and Oren 2007).…”

Section: Synergistic Enhancement Of the Brca1 Brct Domain Transcriptimentioning

confidence: 99%

“…), MEF(CARM1 KI) (with a R169A mutation that eliminates methyltransferase activity), MEF(CARM1 rescued; i.e., with the knockout reversed by Flipase) (Yadav et al 2003;Cheng et al 2007;Kim et al 2010), and 293T cells were maintained in DMEM supplemented with 10% fetal bovine serum. Transfections were performed with F1 Targefect reagent (Targeting Systems) for 293T cells and with Lipofectamine 2000 (Invitrogen) for MEF cells, according to the manufacturers' protocols as described previously .…”

Section: Mef Wild-type Mef(carm1mentioning

confidence: 99%

Regulated recruitment of tumor suppressor BRCA1 to the p21 gene by coactivator methylation

Lee¹,

Bedford²,

Stallcup³

2011

Genes Dev.

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Tumor suppression by p53 and BRCA1 involves regulation of cell cycle, apoptosis, and DNA repair and is influenced by transcriptional coactivators and post-translational modifications. Here we show that coactivatorassociated arginine methyltransferase 1 (CARM1) methylates Arg 754 in the KIX region of coactivator p300. Methylated p300 and p300 protein fragments are preferentially recognized by BRCT domains of BRCA1, identifying the BRCT domain as a novel methylarginine-binding module. CARM1 and p300 cooperate with BRCA1 and p53 to induce expression of the critical cell cycle and proliferation regulator p21 WAF1/CIP1 in response to DNA damage. This induction was severely attenuated by elimination of CARM1 or its methyltransferase activity, or by mutation of Arg 754 of p300. Absence of CARM1 methyltransferase activity led to failure of cells to arrest in the G1 phase of the cell cycle in response to DNA damage. CARM1 methyltransferase activity was required for induction of some p53 target genes (p21 and Gadd45) but not others (Bax) by DNA damage. Recruitment of BRCA1 to the p53-binding region of the p21 promoter in response to DNA damage required methylation of Arg 754 of p300 by CARM1. Thus, coactivator methylation may be crucial for fine-tuning the tumor suppressor function of BRCA1 and other BRCT domain proteins.

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“…Mice with a targeted deletion of Carm1 (Carm1 / ) are small and have defects in the differentiation of multiple cell types including T cells and adipocytes (Kim et al, 2004;Yadav et al, 2008;Yadav et al, 2003). Recently, it has been shown that mice carrying the enzyme-dead form of CARM1 phenocopy the Carm1 knockout, suggesting that CARM1 requires enzymatic activity for its known cellular functions (Kim et al, 2009). Carm1 knockout animals die shortly after birth and suffer from respiratory distress.…”

Section: Introductionmentioning

confidence: 99%

CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells

et al. 2010

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SUMMARYCoactivator-associated arginine methyltransferase I (CARM1; PRMT4) regulates gene expression by multiple mechanisms including methylation of histones and coactivation of steroid receptor transcription. Mice lacking CARM1 are small, fail to breathe and die shortly after birth, demonstrating the crucial role of CARM1 in development. In adults, CARM1 is overexpressed in human grade-III breast tumors and prostate adenocarcinomas, and knockdown of CARM1 inhibits proliferation of breast and prostate cancer cell lines. Based on these observations, we hypothesized that loss of CARM1 in mouse embryos would inhibit pulmonary cell proliferation, resulting in respiratory distress. By contrast, we report here that loss of CARM1 results in hyperproliferation of pulmonary epithelial cells during embryonic development. The lungs of newborn mice lacking CARM1 have substantially reduced airspace compared with their wild-type littermates. In the absence of CARM1, alveolar type II cells show increased proliferation. Electron microscopic analyses demonstrate that lungs from mice lacking CARM1 have immature alveolar type II cells and an absence of alveolar type I cells. Gene expression analysis reveals a dysregulation of cell cycle genes and markers of differentiation in the Carm1 knockout lung. Furthermore, there is an overlap in gene expression in the Carm1 knockout and the glucocorticoid receptor knockout lung, suggesting that hyperproliferation and lack of maturation of the alveolar cells are at least in part caused by attenuation of glucocorticoid-mediated signaling. These results demonstrate for the first time that CARM1 inhibits pulmonary cell proliferation and is required for proper differentiation of alveolar cells. ) are small and have defects in the differentiation of multiple cell types including T cells and adipocytes (Kim et al., 2004;Yadav et al., 2008;Yadav et al., 2003). Recently, it has been shown that mice carrying the enzyme-dead form of CARM1 phenocopy the Carm1 knockout, suggesting that CARM1 requires enzymatic activity for its known cellular functions (Kim et al., 2009). Carm1 knockout animals die shortly after birth and suffer from respiratory distress. Carm1/ animals fail to inflate their lungs after birth, and have reduced alveolar air space compared with wild-type littermates. These observations suggest that CARM1 is an important regulator of lung development. However, detailed studies of CARM1 expression and function in lung have not been described. Development of the distal lung and alveolar sacculation are tightly regulated by a myriad of hormone signals and a cascade of interacting transcription factor pathways that are just beginning to be elucidated (Cardoso and Lu, 2006;Maeda et al., 2007). Progenitor cells in the distal lung differentiate to multiple types including Clara bronchiole epithelial cells and alveolar type II (AT2) cells. AT2 cells are cuboidal and located in the alveolar sacs that produce the surfactant required to reduce surface tension for these sacs to fill with air. AT2 cell...

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Enzymatic Activity Is Required for the in Vivo Functions of CARM1

Cited by 65 publications

References 37 publications

Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

Histone H3R17me2a mark recruits human RNA Polymerase-Associated Factor 1 Complex to activate transcription

Regulated recruitment of tumor suppressor BRCA1 to the p21 gene by coactivator methylation

CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells

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