9 results on '"Bing-ling Peng"'
Search Results
2. The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis
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Hai‐feng Shen, Wen‐juan Zhang, Ying Huang, Yao‐hui He, Guo‐sheng Hu, Lei Wang, Bing‐ling Peng, Jia Yi, Ting‐ting Li, Rui Rong, Xiao‐yan Chen, Jun‐yi Liu, Wen‐juan Li, Kenny Ohgi, Shao‐Wei Li, Michael G. Rosenfeld, and Wen Liu
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breast cancer ,estrogen and estrogen receptor ,Jumonji C domain‐containing protein ,type I interferon ,Science - Abstract
Abstract Emerging evidence suggested that epigenetic regulators can exhibit both activator and repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in specific cellular contexts remains elusive. Here, it is reported that KDM5C, a repressive histone demethylase, unexpectedly activates estrogen receptor alpha (ERα)‐target genes, and meanwhile suppresses type I interferons (IFNs) and IFN‐stimulated genes (ISGs) to promote ERα‐positive breast cancer cell growth and tumorigenesis. KDM5C‐interacting protein, ZMYND8, is found to be involved in both processes. Mechanistically, KDM5C binds to active enhancers and recruits the P‐TEFb complex to activate ERα‐target genes, while inhibits TBK1 phosphorylation in the cytosol to repress type I IFNs and ISGs. Pharmacological inhibition of both ERα and KDM5C is effective in inhibiting cell growth and tumorigenesis. Taken together, it is revealed that the dual activator and repressor nature of an epigenetic regulator together contributes to cancer development.
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- 2021
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3. A hypermethylation strategy utilized by enhancer-bound CARM1 to promote estrogen receptor α-dependent transcriptional activation and breast carcinogenesis
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Ting Ran, Rong-quan Xiao, Wen Liu, Wen-Juan Li, Hai-feng Shen, Xiang Gao, Zi-Rui Wang, Bing-Lan Xie, Jiancheng Ding, Tian-yi Ye, Yaohui He, Bing-ling Peng, and Weiwei Gao
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Transcriptional Activation ,0301 basic medicine ,Protein-Arginine N-Methyltransferases ,CARM1 ,Mice, Nude ,Medicine (miscellaneous) ,Estrogen receptor ,Breast Neoplasms ,Biology ,Arginine ,Methylation ,Chromatin remodeling ,tudor domain-containing protein ,Gene Knockout Techniques ,Mice ,03 medical and health sciences ,breast cancer ,0302 clinical medicine ,Protein arginine methyltransferase ,Coactivator ,Protein methylation ,Animals ,Humans ,RNA-Seq ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Cell Proliferation ,Mice, Inbred BALB C ,Mediator Complex ,Estrogen Receptor alpha ,Proteins ,Estrogens ,Xenograft Model Antitumor Assays ,Chromatin ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,Enhancer Elements, Genetic ,030104 developmental biology ,protein arginine methylation ,030220 oncology & carcinogenesis ,DNA methylation ,MCF-7 Cells ,Cancer research ,Chromatin Immunoprecipitation Sequencing ,Female ,Estrogen receptor alpha ,Research Paper ,estrogen receptor ,Protein Binding - Abstract
While protein arginine methyltransferases (PRMTs) and PRMT-catalyzed protein methylation have been well-known to be involved in a myriad of biological processes, their functions and the underlying molecular mechanisms in cancers, particularly in estrogen receptor alpha (ERα)-positive breast cancers, remain incompletely understood. Here we focused on investigating PRMT4 (also called coactivator associated arginine methyltransferase 1, CARM1) in ERα-positive breast cancers due to its high expression and the associated poor prognosis. Methods: ChIP-seq and RNA-seq were employed to identify the chromatin-binding landscape and transcriptional targets of CARM1, respectively, in the presence of estrogen in ERα-positive MCF7 breast cancer cells. High-resolution mass spectrometry analysis of enriched peptides from anti-monomethyl- and anti-asymmetric dimethyl-arginine antibodies in SILAC labeled wild-type and CARM1 knockout cells were performed to globally map CARM1 methylation substrates. Cell viability was measured by MTS and colony formation assay, and cell cycle was measured by FACS analysis. Cell migration and invasion capacities were examined by wound-healing and trans-well assay, respectively. Xenograft assay was used to analyze tumor growth in vivo. Results: CARM1 was found to be predominantly and specifically recruited to ERα-bound active enhancers and essential for the transcriptional activation of cognate estrogen-induced genes in response to estrogen treatment. Global mapping of CARM1 substrates revealed that CARM1 methylated a large cohort of proteins with diverse biological functions, including regulation of intracellular estrogen receptor-mediated signaling, chromatin organization and chromatin remodeling. A large number of CARM1 substrates were found to be exclusively hypermethylated by CARM1 on a cluster of arginine residues. Exemplified by MED12, hypermethylation of these proteins by CARM1 served as a molecular beacon for recruiting coactivator protein, tudor-domain-containing protein 3 (TDRD3), to CARM1-bound active enhancers to activate estrogen/ERα-target genes. In consistent with its critical role in estrogen/ERα-induced gene transcriptional activation, CARM1 was found to promote cell proliferation of ERα-positive breast cancer cells in vitro and tumor growth in mice. Conclusions: our study uncovered a “hypermethylation” strategy utilized by enhancer-bound CARM1 in gene transcriptional regulation, and suggested that CARM1 can server as a therapeutic target for breast cancer treatment.
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- 2020
4. Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth
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Helen He Zhu, Feng Ye, Ming-feng Huang, Yaohui He, Hai-hua Huang, Bing-Lan Xie, Jing-Jing Yang, Wen-Juan Li, Yi-An Lin, Bing-ling Peng, Ting Ran, Wen Liu, Guo-sheng Hu, and Xiang Gao
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Male ,Proteomics ,0301 basic medicine ,Protein-Arginine N-Methyltransferases ,Methyltransferase ,Arginine ,Science ,Heterogeneous Nuclear Ribonucleoprotein A1 ,General Physics and Astronomy ,Breast Neoplasms ,RNA-binding proteins ,RNA-binding protein ,Methylation ,Article ,General Biochemistry, Genetics and Molecular Biology ,Substrate Specificity ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Humans ,Amino Acid Sequence ,Enzyme Inhibitors ,RNA, Small Interfering ,Regulation of gene expression ,Multidisciplinary ,Chemistry ,Gene Expression Profiling ,Cell Cycle ,Alternative splicing ,Prostatic Neoplasms ,General Chemistry ,Cell biology ,Gene Expression Regulation, Neoplastic ,Alternative Splicing ,HEK293 Cells ,030104 developmental biology ,030220 oncology & carcinogenesis ,RNA splicing ,DNA methylation ,Spliceosomes ,Female ,Colorectal Neoplasms ,Protein Processing, Post-Translational ,Protein Binding - Abstract
Numerous substrates have been identified for Type I and II arginine methyltransferases (PRMTs). However, the full substrate spectrum of the only type III PRMT, PRMT7, and its connection to type I and II PRMT substrates remains unknown. Here, we use mass spectrometry to reveal features of PRMT7-regulated methylation. We find that PRMT7 predominantly methylates a glycine and arginine motif; multiple PRMT7-regulated arginine methylation sites are close to phosphorylations sites; methylation sites and proximal sequences are vulnerable to cancer mutations; and methylation is enriched in proteins associated with spliceosome and RNA-related pathways. We show that PRMT4/5/7-mediated arginine methylation regulates hnRNPA1 binding to RNA and several alternative splicing events. In breast, colorectal and prostate cancer cells, PRMT4/5/7 are upregulated and associated with high levels of hnRNPA1 arginine methylation and aberrant alternative splicing. Pharmacological inhibition of PRMT4/5/7 suppresses cancer cell growth and their co-inhibition shows synergistic effects, suggesting them as targets for cancer therapy., Arginine methyltransferases (PRMTs) are involved in the regulation of various physiological and pathological conditions. Using proteomics, the authors here profile the methylation substrates of PRMTs 4, 5 and 7 and characterize the roles of these enzymes in cancer-associated splicing regulation.
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- 2021
5. Virtual Screening with a Structure-Based Pharmacophore Model to Identify Small-Molecule Inhibitors of CARM1
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Shuai Lu, Wen-Juan Li, Tao Lu, Ting Ran, Bing-ling Peng, Bing-Lan Xie, and Wen Liu
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Protein-Arginine N-Methyltransferases ,CARM1 ,Protein family ,Protein Conformation ,General Chemical Engineering ,Drug Evaluation, Preclinical ,Druggability ,Library and Information Sciences ,Ligands ,01 natural sciences ,User-Computer Interface ,Protein structure ,0103 physical sciences ,Humans ,Enzyme Inhibitors ,Binding site ,Virtual screening ,Binding Sites ,010304 chemical physics ,Chemistry ,General Chemistry ,Small molecule ,0104 chemical sciences ,Computer Science Applications ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Biochemistry ,MCF-7 Cells ,Pharmacophore - Abstract
CARM1 (coactivator-associated arginine methyltransferase 1), also known as PRMT4 (protein arginine N-methyltransferase 4), belongs to the protein arginine methyltransferase (PRMT) family, which has emerged as a potential anticancer drug target. To discover new CARM1 inhibitors, we performed virtual screening against the substrate-binding site in CARM1. Structure-based pharmacophore models, which were generated according to three druggable subpockets embedding critical residues for ligand binding, were applied for virtual screening. The importance of the solvent-exposed substrate-binding cavity was highlighted due to significant hydrophobicity. Aided by molecular docking, 15 compounds structurally distinct from known CARM1 inhibitors were selected to evaluate their inhibitory effects on CARM1 methyltransferase activity, which resulted in seven compounds exhibiting micromolar inhibition, with selectivity over other members in the PRMT protein family. Moreover, three of them exhibited potent antiproliferation activities in breast cancer cells. Particularly, compound NO.2 exhibited potent activity both in vitro and in cultured cells, which will serve as a leading hit for developing CARM1 inhibitors with improved efficacy. The virtual screening strategy in this study will be applicable for the discovery of substrate-competitive inhibitors targeting other members in the PRMT protein family.
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- 2019
6. The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis
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Bing-ling Peng, Jia Yi, Wen-juan Zhang, Shaowei Li, Hai-feng Shen, Ying Huang, Wen-Juan Li, Rui Rong, Michael G. Rosenfeld, Xiao‐yan Chen, Tingting Li, Kenny Ohgi, Yaohui He, Lei Wang, Jun-yi Liu, Guo-sheng Hu, and Wen Liu
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Transcriptional Activation ,Jumonji C domain‐containing protein ,Carcinogenesis ,General Chemical Engineering ,Science ,General Physics and Astronomy ,Medicine (miscellaneous) ,Repressor ,Breast Neoplasms ,02 engineering and technology ,Biology ,010402 general chemistry ,medicine.disease_cause ,01 natural sciences ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,breast cancer ,Cell Line, Tumor ,Transcriptional regulation ,medicine ,Humans ,General Materials Science ,Epigenetics ,Research Articles ,Cell Proliferation ,Histone Demethylases ,Activator (genetics) ,Cell growth ,estrogen and estrogen receptor ,General Engineering ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Cell biology ,Cell Transformation, Neoplastic ,biology.protein ,Demethylase ,type I interferon ,Female ,0210 nano-technology ,Estrogen receptor alpha ,Research Article - Abstract
Emerging evidence suggested that epigenetic regulators can exhibit both activator and repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in specific cellular contexts remains elusive. Here, it is reported that KDM5C, a repressive histone demethylase, unexpectedly activates estrogen receptor alpha (ERα)‐target genes, and meanwhile suppresses type I interferons (IFNs) and IFN‐stimulated genes (ISGs) to promote ERα‐positive breast cancer cell growth and tumorigenesis. KDM5C‐interacting protein, ZMYND8, is found to be involved in both processes. Mechanistically, KDM5C binds to active enhancers and recruits the P‐TEFb complex to activate ERα‐target genes, while inhibits TBK1 phosphorylation in the cytosol to repress type I IFNs and ISGs. Pharmacological inhibition of both ERα and KDM5C is effective in inhibiting cell growth and tumorigenesis. Taken together, it is revealed that the dual activator and repressor nature of an epigenetic regulator together contributes to cancer development., A histone demethylase named KDM5C activates estrogen/estrogen receptor alpha‐target genes to promote cancer cell growth, while suppresses type I interferons and interferon‐stimulated genes to escape from immune surveillance. The dual activator and repressor nature of KDM5C together contributes to cancer development.
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- 2020
7. Regulation of Transcription Factor Yin Yang 1 by SET7/9-mediated Lysine Methylation
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Wen-juan Zhang, Hai-feng Shen, Weiwei Gao, Xiao-Nan Wu, Jiancheng Ding, Ming-feng Huang, Xing-yi Shu, Jia Yi, Tao-tao Shi, Huan-teng Xu, Bing-ling Peng, Rong-quan Xiao, Fei-fei Wang, and Wen Liu
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0301 basic medicine ,Methyltransferase ,Transcription, Genetic ,Biology ,Transfection ,Methylation ,Article ,03 medical and health sciences ,Protein Domains ,Transcription (biology) ,Humans ,RNA, Small Interfering ,Transcription factor ,RNA-Directed DNA Methylation ,YY1 Transcription Factor ,Cell Proliferation ,Genetics ,Multidisciplinary ,030102 biochemistry & molecular biology ,Lysine ,EZH2 ,Histone-Lysine N-Methyltransferase ,Recombinant Proteins ,Cell biology ,HEK293 Cells ,030104 developmental biology ,Histone methyltransferase ,embryonic structures ,DNA methylation ,CRISPR-Cas Systems ,Protein Processing, Post-Translational ,HeLa Cells ,Plasmids - Abstract
Yin Yang 1 (YY1) is a multifunctional transcription factor shown to be critical in a variety of biological processes. Although it is regulated by multiple types of post-translational modifications (PTMs), whether YY1 is methylated, which enzyme methylates YY1 and hence the functional significance of YY1 methylation remains completely unknown. Here we reported the first methyltransferase, SET7/9 (KMT7), capable of methylating YY1 at two highly conserved lysine (K) residues, K173 and K411, located in two distinct domains, one in the central glycine-rich region and the other in the very carboxyl-terminus. Functional studies revealed that SET7/9-mediated YY1 methylation regulated YY1 DNA-binding activity both in vitro and at specific genomic loci in cultured cells. Consistently, SET7/9-mediated YY1 methylation was shown to involve in YY1-regulated gene transcription and cell proliferation. Our findings revealed a novel regulatory strategy, methylation by lysine methyltransferase, imposed on YY1 protein and linked YY1 methylation with its biological functions.
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- 2016
8. JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex
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Wen Liu, Wen-juan Zhang, Bing-ling Peng, Rong-quan Xiao, Wen-Juan Li, Michael G. Rosenfeld, Jiancheng Ding, Hai-feng Shen, Yiren Hu, Huang Qixuan, Ying Li, Weiwei Gao, Tian-yi Ye, Yaohui He, Zhi-ying Liu, and Rong Ding
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Transcriptional Activation ,0301 basic medicine ,Jumonji Domain-Containing Histone Demethylases ,Protein-Arginine N-Methyltransferases ,Mice, Nude ,Estrogen receptor ,Breast Neoplasms ,Enhancer RNAs ,Biology ,Gene Expression Regulation, Enzymologic ,Article ,03 medical and health sciences ,Mediator ,Transcriptional regulation ,Animals ,Humans ,Enhancer ,Molecular Biology ,Cell Proliferation ,Regulation of gene expression ,Mice, Inbred BALB C ,Binding Sites ,Mediator Complex ,Estradiol ,Chromatin binding ,Estrogen Receptor alpha ,Cell Biology ,Cell biology ,Gene Expression Regulation, Neoplastic ,Protein Transport ,HEK293 Cells ,030104 developmental biology ,MCF-7 Cells ,Female ,Estrogen receptor alpha ,Protein Binding ,Signal Transduction - Abstract
Whereas the actions of enhancers in gene transcriptional regulation are well established, roles of JmjC domain-containing proteins in mediating enhancer activation remain poorly understood. Here we report that recruitment of the JmjC domain-containing protein 6 (JMJD6) to estrogen receptor alpha (ERα)-bound active enhancers is required for RNA polymerase II recruitment and enhancer RNA production on enhancers, resulting in transcriptional pause release of cognate estrogen target genes. JMJD6 was found to interact with MED12 in the mediator complex to regulate its recruitment. Unexpectedly, JMJD6 is necessary for MED12 to interact with CARM1, which methylates MED12 at multiple arginine sites and regulates its chromatin binding. Consistent with its role in transcriptional activation, JMJD6 is required for estrogen/ERα-induced breast cancer cell growth and tumorigenesis. Our data have uncovered a critical regulator of estrogen/ERα-induced enhancer, coding gene activation and breast cancer cell potency, providing a potential therapeutic target of ER-positive breast cancers.
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- 2018
9. Arginine methylation of HSP70 regulates retinoid acid-mediated RARβ2 gene activation.
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Wei-wei Gao, Rong-quan Xiao, Bing-ling Peng, Huan-teng Xu, Hai-feng Shen, Ming-feng Huang, Tao-tao Shi, Jia Yi, Wen-juan Zhang, Xiao-nan Wu, Xiang Gao, Xiang-zhi Lin, Dorrestein, Pieter C., Rosenfeld, Michael G., and Wen Liu
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ARGININE ,METHYLATION ,HSP70 heat-shock proteins ,RETINOIDS ,HISTONES ,MOLECULAR chaperones ,GENETIC transcription - Abstract
Although "histone" methyltransferases and demethylases are well established to regulate transcriptional programs and to use nonhistone proteins as substrates, their possible roles in regulation of heat-shock proteins in the nucleus have not been investigated. Here, we report that a highly conserved arginine residue, R469, in HSP70 (heat-shock protein of 70 kDa) proteins, an evolutionarily conserved protein family of ATP-dependent molecular chaperone, was monomethylated (me1), at least partially, by coactivatorassociated arginine methyltransferase 1/protein arginine methyltransferase 4 (CARM1/PRMT4) and demethylated by jumonjidomain- containing 6 (JMJD6), both in vitro and in cultured cells. Functional studies revealed that HSP70 could directly regulate retinoid acid (RA)-induced retinoid acid receptor β2 (RARβ2) gene transcription through its binding to chromatin, with R469me1 being essential in this process. HSP70's function in gene transcriptional regulation appears to be distinct from its protein chaperon activity. R469me1 was shown to mediate the interaction between HSP70 and TFIIH, which involves in RNA polymerase II phosphorylation and thus transcriptional initiation. Our findings expand the repertoire of nonhistone substrates targeted by PRMT4 and JMJD6, and reveal a new function of HSP70 proteins in gene transcription at the chromatin level aside from its classic role in protein folding and quality control. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
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