Dataset Information

Regulation of estrogen receptor ? by histone methyltransferase SMYD2-mediated protein methylation.

ABSTRACT: Estrogen receptor alpha (ER?) is a ligand-activated transcription factor. Upon estrogen stimulation, ER? recruits a number of coregulators, including both coactivators and corepressors, to the estrogen response elements, modulating gene activation or repression. Most coregulator complexes contain histone-modifying enzymes to control ER? target gene expression in an epigenetic manner. In addition to histones, these epigenetic modifiers can modify nonhistone proteins including ER?, thereby constituting another layer of transcriptional regulation. Here we show that SET and MYND domain containing 2 (SMYD2), a histone H3K4 and H3K36 methyltransferase, directly methylates ER? protein at lysine 266 (K266) both in vitro and in cells. In breast cancer MCF7 cells, SMYD2 attenuates the chromatin recruitment of ER? to prevent ER? target gene activation under an estrogen-depleted condition. Importantly, the SMYD2-mediated repression of ER? target gene expression is mediated by the methylation of ER? at K266 in the nucleus, but not the methylation of histone H3K4. Upon estrogen stimulation, ER?-K266 methylation is diminished, thereby enabling p300/cAMP response element-binding protein-binding protein to acetylate ER? at K266, which is known to promote ER? transactivation activity. Our study identifies a previously undescribed inhibitory methylation event on ER?. Our data suggest that the dynamic cross-talk between SMYD2-mediated ER? protein methylation and p300/cAMP response element-binding protein-binding protein-dependent ER? acetylation plays an important role in fine-tuning the functions of ER? at chromatin and the estrogen-induced gene expression profiles.

SUBMITTER: Zhang X

PROVIDER: S-EPMC3808627 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Regulation of estrogen receptor α by histone methyltransferase SMYD2-mediated protein methylation.

Zhang Xi X Tanaka Kaori K Yan Jiusheng J Li Jing J Peng Danni D Jiang Yuanyuan Y Yang Zhe Z Barton Michelle C MC Wen Hong H Shi Xiaobing X

Proceedings of the National Academy of Sciences of the United States of America 20131007 43

Estrogen receptor alpha (ERα) is a ligand-activated transcription factor. Upon estrogen stimulation, ERα recruits a number of coregulators, including both coactivators and corepressors, to the estrogen response elements, modulating gene activation or repression. Most coregulator complexes contain histone-modifying enzymes to control ERα target gene expression in an epigenetic manner. In addition to histones, these epigenetic modifiers can modify nonhistone proteins including ERα, thereby constit ...[more]

PMID: 24101509

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Project description:Heart failure remains a major cause of hospitalization and death worldwide. Heart failure can be caused by abnormalities in the epigenome resulting from dysregulation of histone-modifying enzymes. While chromatin enzymes catalyzing lysine acetylation and methylation of histones have been the topic of many investigations, the role of arginine methyltransferases has been overlooked. In an effort to understand regulatory mechanisms implicated in cardiac hypertrophy and heart failure, we assessed the expression of protein arginine methyltransferases (PRMTs) in the left ventricle of failing human hearts and control hearts. Our results show a significant up-regulation of protein arginine methyltransferase 6 (PRMT6) in failing human hearts compared to control hearts, which also occurs in the early phase of cardiac hypertrophy in mouse hearts subjected to pressure overload hypertrophy induced by trans-aortic constriction (TAC), and in neonatal rat ventricular myocytes (NRVM) stimulated with the hypertrophic agonist phenylephrine (PE). These changes are associated with a significant increase in arginine 2 asymmetric methylation of histone H3 (H3R2Me2a) and reduced lysine 4 tri-methylation of H3 (H3K4Me3) observed both in NRVM and in vivo. Importantly, forced expression of PRMT6 in NRVM enhances the expression of the hypertrophic marker, atrial natriuretic peptide (ANP). Conversely, specific silencing of PRMT6 reduces ANP protein expression and cell size, indicating that PRMT6 is critical for the PE-mediated hypertrophic response. Silencing of PRMT6 reduces H3R2Me2a, a mark normally associated with transcriptional repression. Furthermore, evaluation of cardiac contractility and global ion channel activity in live NRVM shows a striking reduction of spontaneous beating rates and prolongation of extra-cellular field potentials in cells expressing low-level PRMT6. Altogether, our results indicate that PRMT6 is a critical regulator of cardiac hypertrophy, implicating H3R2Me2a as an important histone modification. This study identifies PRMT6 as a new epigenetic regulator and suggests a new point of control in chromatin to inhibit pathological cardiac remodeling.

Dataset Information

Regulation of estrogen receptor ? by histone methyltransferase SMYD2-mediated protein methylation.

Publications

Regulation of estrogen receptor α by histone methyltransferase SMYD2-mediated protein methylation.

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