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Differential CARM1 expression in prostate and colorectal cancers
Young-Rang Kim, Byung Lee, Ra-Young Park, Nguyen Nguyen, Jeong A Bae, Dong Kwon, Chaeyong Jung
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-197
Abstract: Tissue microarray was used to determine the pattern of expression of CARM1 in human cancers by immunohistochemistry. CARM1 expression was also evaluated in prostate and colorectal surgical specimens and the clinical records of all cases were reviewed. In addition, a reporter transcription assay using the prostate-specific antigen (PSA) promoter was used to identify the signaling pathways involved in non-hormone-mediated signal activation associated with CARM1.The tissue microarray showed that CARM1 was particularly overexpressed in the colorectal cancers while CARM1 expression was not prevalent in the prostate and breast cancers. Further studies using surgical specimens demonstrated that CARM1 was highly overexpressed in 75% of colorectal cancers (49 out of 65) but not in the androgen-independent PCa. In addition, CARM1's coactivating effect on the entire PSA promoter was very limited in both androgen-dependent and androgen-independent PCa cells. These results suggest that there are other factors associated with CARM1 expression in PSA regulation. Indeed, CARM1 significantly regulated both p53 and NF-κB target gene transcription.The results of this study suggest that, in addition to its role in activation of steroid receptors, CARM1 functions as a transcriptional modulator by altering the activity of many transcriptional factors, especially with regard to androgen independent PCa and colorectal cancers.CARM1 is a protein with arginine-specific histone methyltransferase activity [1]; it initially was described as a transcriptional activator of the p160 family of nuclear receptor-associated proteins (Src-1, GRIP1/TIF2/Src-2, ACTR/AIB1/SRC-3)[2-5]. The p160 coactivators act as primary coactivators through direct binding to the C-terminal region of nuclear receptors in a ligand-dependent manner. The p160 coactivators are involved in transcriptional activation by bringing secondary activators with them to the promoter. While p300 and CBP bind to the activation domain (AD
MicroRNA-181 Regulates CARM1 and Histone Aginine Methylation to Promote Differentiation of Human Embryonic Stem Cells  [PDF]
Zhenyu Xu, Junfeng Jiang, Chen Xu, Yue Wang, Lei Sun, Xiaocan Guo, Houqi Liu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053146
Abstract: As a novel epigenetic mechanism, histone H3 methylation at R17 and R26, which is mainly catalyzed by coactivator-associated protein arginine methyltransferase 1 (CARM1), has been reported to modulate the transcription of key pluripotency factors and to regulate pluripotency in mouse embryos and mouse embryonic stem cells (mESCs) in previous studies. However, the role of CARM1 in human embryonic stem cells (hESCs) and the regulatory mechanism that controls CARM1 expression during ESCs differentiation are presently unknown. Here, we demonstrate that CARM1 plays an active role in the resistance to differentiation in hESCs by regulating pluripotency genes in response to BMP4. In a functional screen, we identified the miR-181 family as a regulator of CARM1 that is induced during ESC differentiation and show that endogenous miR-181c represses the expression of CARM1. Depletion of CARM1 or enforced expression of miR-181c inhibits the expression of pluripotency genes and induces differentiation independent of BMP4, whereas overexpression of CARM1 or miR-181c inhibitor elevates Nanog and impedes differentiation. Furthermore, expression of CARM1 rescue constructs inhibits the effect of miR-181c overexpression in promoting differentiation. Taken together, our findings demonstrate the importance of a miR-181c-CARM1 pathway in regulating the differentiation of hESCs.
The Methyltransferases PRMT4/CARM1 and PRMT5 Control Differentially Myogenesis in Zebrafish  [PDF]
Julie Batut, Carine Duboé, Laurence Vandel
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025427
Abstract: In vertebrates, skeletal myogenesis involves the sequential activation of myogenic factors to lead ultimately to the differentiation into slow and fast muscle fibers. How transcriptional co-regulators such as arginine methyltransferases PRMT4/CARM1 and PRMT5 control myogenesis in vivo remains poorly understood. Loss-of-function experiments using morpholinos against PRMT4/CARM1 and PRMT5 combined with in situ hybridization, quantitative polymerase chain reaction, as well as immunohistochemistry indicate a positive, but differential, role of these enzymes during myogenesis in vivo. While PRMT5 regulates myod, myf5 and myogenin expression and thereby slow and fast fiber formation, PRMT4/CARM1 regulates myogenin expression, fast fiber formation and does not affect slow fiber formation. However, our results show that PRMT4/CARM1 is required for proper slow myosin heavy chain localization. Altogether, our results reveal a combinatorial role of PRMT4/CARM1 and PRMT5 for proper myogenesis in zebrafish.
Kv4.2 Mediates Histamine Modulation of Preoptic Neuron Activity and Body Temperature  [PDF]
Jasmine Sethi, Manuel Sanchez-Alavez, Iustin V. Tabarean
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0029134
Abstract: Histamine regulates arousal, circadian rhythms, and thermoregulation. Activation of H3 histamine receptors expressed by preoptic GABAergic neurons results in a decrease of their firing rate and hyperthermia. Here we report that an increase in the A-type K+ current in preoptic GABAergic neurons in response to activation of H3 histamine receptors results in decreased firing rate and hyperthermia in mice. The Kv4.2 subunit is required for these actions in spite of the fact that Kv4.2?/? preoptic GABAergic neurons display A-type currents and firing characteristics similar to those of wild-type neurons. This electrical remodeling is achieved by robust upregulation of the expression of the Kv4.1 subunit and of a delayed rectifier current. Dynamic clamp experiments indicate that enhancement of the A-type current by a similar amount to that induced by histamine is sufficient to mimic its robust effect on firing rates. These data indicate a central role played by the Kv4.2 subunit in histamine regulation of body temperature and its interaction with pERK1/2 downstream of the H3 receptor. We also reveal that this pathway provides a mechanism for selective modulation of body temperature at the beginning of the active phase of the circadian cycle.
Arginine methyltransferase CARM1/PRMT4 regulates endochondral ossification
Tatsuo Ito, Neelu Yadav, Jaeho Lee, Takayuki Furumatsu, Satoshi Yamashita, Kenji Yoshida, Noboru Taniguchi, Megumi Hashimoto, Megumi Tsuchiya, Toshifumi Ozaki, Martin Lotz, Mark T Bedford, Hiroshi Asahara
BMC Developmental Biology , 2009, DOI: 10.1186/1471-213x-9-47
Abstract: CARM1-null mice display delayed endochondral ossification and decreased chondrocyte proliferation. Conversely, cartilage development of CARM1 transgenic mice was accelerated. CARM1 specifically methylates Sox9 at its HMG domain in vivo and in vitro. Arg-methylation of Sox9 by CARM1 disrupts interaction of Sox9 with beta-catenin, regulating Cyclin D1 expression and cell cycle progression of chondrocytes.These results establish a role for CARM1 as an important regulator of chondrocyte proliferation during embryogenesis.The precise patterning of the developing skeletal framework relies on the appropriate control of chondrogenesis, a multistep process during which mesenchymal cells differentiate into chondrocytes[1,2]. This process is tightly regulated by transcription factors, including Sox9 [3-6]. Mice lacking Sox9 display distortion of numerous cartilage-derived skeletal structures[7]. In addition, mice overexpressing Sox9 in chondrocytes show dwarfism with decreased chondrocyte proliferation and delayed endochondral bone formation[1]. However, the precise mechanism how Sox9 regulates chondrogenesis both spatially and temporally is still largely unknown.CARM1 belongs to a family of arginine-specific protein methyltransferases (PRMTs), which includes at least eight members (PRMT1-8) [8]. All PRMT family members share a core arginine methyltransferase region composed of a conserved Ado-Met binding domain and a more divergent C-terminal domain. CARM1 has been shown to synergistically activate transcription with nuclear receptors in combination with other coactivators, such as p160 family, p300/CBP and SRC-2/TIF2/GRIP1[9,10]. After recruitment to promoters of steroid-responsive genes, CARM1 methylates specific residues (Arg17 and Arg26) at the N-terminus of histone H3 resulting in transcriptional activation[11,12].To examine the potential role of CARM1 in skeletal development, we analyzed CARM1 null embryos, which die immediately after birth as reported[13]. At E14.5, be
Disruption of Histone Modification and CARM1 Recruitment by Arsenic Represses Transcription at Glucocorticoid Receptor-Regulated Promoters  [PDF]
Fiona D. Barr, Lori J. Krohmer, Joshua W. Hamilton, Lynn A. Sheldon
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006766
Abstract: Chronic exposure to inorganic arsenic (iAs) found in the environment is one of the most significant and widespread environmental health risks in the U.S. and throughout the world. It is associated with a broad range of health effects from cancer to diabetes as well as reproductive and developmental anomalies. This diversity of diseases can also result from disruption of metabolic and other cellular processes regulated by steroid hormone receptors via aberrant transcriptional regulation. Significantly, exposure to iAs inhibits steroid hormone-mediated gene activation. iAs exposure is associated with disease, but is also used therapeutically to treat specific cancers complicating an understanding of iAs action. Transcriptional activation by steroid hormone receptors is accompanied by changes in histone and non-histone protein post-translational modification (PTM) that result from the enzymatic activity of coactivator and corepressor proteins such as GRIP1 and CARM1. This study addresses how iAs represses steroid receptor-regulated gene transcription. PTMs on histones H3 and H4 at the glucocorticoid receptor (GR)-activated mouse mammary tumor virus (MMTV) promoter were identified by chromatin immunoprecipitation analysis following exposure to steroid hormone±iAs. Histone H3K18 and H3R17 amino acid residues had significantly different patterns of PTMs after treatment with iAs. Promoter interaction of the coactivator CARM1 was disrupted, but the interaction of GRIP1, a p160 coactivator through which CARM1 interacts with a promoter, was intact. Over-expression of CARM1 was able to fully restore and GRIP1 partially restored iAs-repressed transcription indicating that these coactivators are functionally associated with iAs-mediated transcriptional repression. Both are essential for robust transcription at steroid hormone regulated genes and both are associated with disease when inappropriately expressed. We postulate that iAs effects on CARM1 and GRIP1 may underlie some of its therapeutic effects and as well be associated with its toxic effects.
A Role for CARM1-Mediated Histone H3 Arginine Methylation in Protecting Histone Acetylation by Releasing Corepressors from Chromatin  [PDF]
Jing Wu, Nan Cui, Rui Wang, Jiwen Li, Jiemin Wong
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034692
Abstract: Arginine methylation broadly occurs in histones and has been linked to transcriptional regulation, cell cycle regulation and DNA repair. While numerous proteins (histone code effectors) that specifically recognize or read the methylated lysine residues in core histones have been identified, little is known for effectors specific for methylated arginines in histones. In this study, we attempted to identify effector(s) recognizing asymmetrically methylated R17 and R26 in H3, which are catalyzed by CARM1/PRMT4, through an unbiased biochemical approach. Although we have yet to identify such effector using this approach, we find that these modifications function cooperatively with histone acetylation to inhibit the binding of the nucleosome remodeling and deacetylase complex (NuRD) and TIF1 family corepressors to H3 tail in vitro. In support of this finding, we show that overexpression of CARM1 in 293 T cells leads to reduced association of NuRD with chromatin, whereas knockdown of CARM1 in HeLa cells leads to increased association of NuRD with chromatin and decreased level of histone acetylation. Furthermore, in the Carm1?/? MEF cells there is an increased association of NuRD and TIF1β with chromatin and a global decrease in histone acetylation. By chromatin immunoprecipitation assay, we show that overexpression of CARM1 results in reduced association of NuRD complex and TIF1β with an episomal reporter and that CARM1 is required in MEF cells for LPS-induced dissociation of NuRD from a NF-κb target gene. Taking together, our study provides evidence for a role of CARM1-mediated arginine methylation in regulation of histone acetylation and transcription: facilitating transcription by discharging corepressors from chromatin.
Evidence That SOX2 Overexpression Is Oncogenic in the Lung  [PDF]
Yun Lu,Christopher Futtner,Jason R. Rock,Xia Xu,Walter Whitworth,Brigid L. M. Hogan,Mark W. Onaitis
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011022
Abstract: SOX2 (Sry-box 2) is required to maintain a variety of stem cells, is overexpressed in some solid tumors, and is expressed in epithelial cells of the lung.
Hypermethylation of SOX2 Promoter in Endometrial Carcinogenesis  [PDF]
Oscar Gee-Wan Wong,Zhen Huo,Michelle Kwan-Yee Siu,HuiJuan Zhang,LiLi Jiang,Ester Shuk-Ying Wong,Annie Nga-Yin Cheung
Obstetrics and Gynecology International , 2010, DOI: 10.1155/2010/682504
Abstract: This paper aimed at investigating the expression and methylation profiles of SOX2, a gene coding for the stem cell-related transcription factor SOX2, in endometrial carcinomas. By methylation-specific polymerase chain reaction (MS-PCR), the methylation status of SOX2 promoter region in 72 endometrial carcinomas and 12 normal endometrial samples was examined. Methylated allele was found in 37.5% (27/72) of endometrial carcinomas but only in 8.3% (1/12) of normal endometrial, significantly more frequent in cancers ( ). SOX2 mRNA level was significantly reduced in endometrial carcinoma compared with nonneoplastic endometrium ( ). A significant correlation between SOX2 mRNA expression and hypermethylation of SOX2 was found ( ). Hypermethylation of SOX2 tended to be more frequently found in type II serous or clear cell adenocarcinoma. SOX2 methylation was also significantly correlated with shorter survival of patients ( ). In conclusion, epigenetic mechanisms may play a crucial role on the transcriptional regulation of SOX2 and loss of SOX2 expression may be related to endometrial carcinogenesis. 1. Introduction Endometrial cancer is the most common cancer found in the female genital tract worldwide [1]. Although endometrial cancers generally show favorable prognosis, the incidence is on the rising trend in North America, Europe, and Asia [2, 3]. There are two major types of endometrial carcinomas exhibiting different histopathology, cell biology, clinical course, and underling genetic alterations [4]. Approximately 70–80% endometrial cancers show endometrioid differentiation and were designated as Type I carcinomas. They are often preceded by premalignant endometrial hyperplasia, which is presumably caused by long-duration unopposed oestrogenic stimulation. Type I carcinomas generally have favorable outcome. Common genetic changes of Type I carcinomas include mutations of K-RAS and PTEN genes, microsatellite instability (MSI) and alteration of beta-catenin [4]. Type II carcinomas are poorly differentiated. In contrast to Type I carcinomas, these tumors are not oestrogen driven and often arise in a background of atrophic endometrium. Type II carcinomas also exhibit a more aggressive clinical course and poorer prognosis than Type I carcinomas. Common genetic changes include mutations of TP53 and CDH1 (E-cadherin) genes [4]. Despite the recent advances in molecular diagnostics, the most important factors in predicting patient prognosis remain to be tumor grade, stage, and subtypes [5, 6]. Sox proteins are transcription factors related by a 79-amino acid
Sox2 Uses Multiple Domains to Associate with Proteins Present in Sox2-Protein Complexes  [PDF]
Jesse L. Cox,Sunil K. Mallanna,Xu Luo,Angie Rizzino
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015486
Abstract: Master regulators, such as Sox2, Oct4 and Nanog, control complex gene networks necessary for the self-renewal and pluripotency of embryonic stem cells (ESC). These master regulators associate with co-activators and co-repressors to precisely control their gene targets. Recent studies using proteomic analysis have identified a large, diverse group of co-activators and co-repressors that associate with master regulators, including Sox2. In this report, we examined the size distribution of nuclear protein complexes containing Sox2 and its associated proteins HDAC1, Sall4 and Lin28. Interestingly, we determined that Sox2 and HDAC1 associate with protein complexes that vary greatly in size; whereas, Lin28 primarily associates with smaller complexes, and Sall4 primarily associates with larger complexes. Additionally, we examined the domains of Sox2 necessary to mediate its association with its partner proteins Sall4, HDAC1 and HDAC2. We determined that Sox2 uses multiple and distinct domains to associate with its partner proteins. We also examined the domains of Sox2 necessary to mediate its self-association, and we determined that Sox2 self-association is mediated through multiple domains. Collectively, these studies provide novel insights into how Sox2 is able to associate with a wide array of nuclear proteins that control gene transcription.
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