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Jinrong Min - One of the best experts on this subject based on the ideXlab platform.
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Epigenetic targets and drug discovery Part 2: Histone Demethylation and DNA methylation
Pharmacology & Therapeutics, 2015Co-Authors: Ke Liu, Yanli Liu, Johnathan L. Lau, Jinrong MinAbstract:Chromatin structure is dynamically modulated by various chromatin modifications, such as Histone/DNA methylation and Demethylation. We have reviewed Histone methyltransferases and methyllysine binders in terms of small molecule screening and drug discovery in the first part of this review series. In this part, we will summarize recent progress in chemical probe and drug discovery of Histone demethylases and DNA methyltransferases. Histone Demethylation and DNA methylation have attracted a lot of attention regarding their biology and disease implications. Correspondingly, many small molecule compounds have been designed to modulate the activity of Histone demethylases and DNA methyltransferases, and some of them have been developed into therapeutic drugs or put into clinical trials.
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structure and function of dioxygenases in Histone Demethylation and dna rna Demethylation
IUCrJ, 2014Co-Authors: Cheng Dong, Jinrong Min, Heng Zhang, Cheryl H. ArrowsmithAbstract:Iron(II) and 2-oxoglutarate (2OG)-dependent dioxygenases involved in Histone and DNA/RNA Demethylation convert the cosubstrate 2OG and oxygen to succinate and carbon dioxide, resulting in hydroxylation of the methyl group of the substrates and subsequent Demethylation. Recent evidence has shown that these 2OG dioxygenases play vital roles in a variety of biological processes, including transcriptional regulation and gene expression. In this review, the structure and function of these dioxygenases in Histone and nucleic acid Demethylation will be discussed. Given the important roles of these 2OG dioxygenases, detailed analysis and comparison of the 2OG dioxygenases will guide the design of target-specific small-molecule chemical probes and inhibitors.
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Structure and function of dioxygenases in Histone Demethylation and DNA/RNA Demethylation
IUCrJ, 2014Co-Authors: Cheng Dong, Heng Zhang, Cheryl H. Arrowsmith, Jinrong MinAbstract:Iron(II) and 2-oxoglutarate (2OG)-dependent dioxygenases involved in Histone and DNA/RNA Demethylation convert the cosubstrate 2OG and oxygen to succinate and carbon dioxide, resulting in hydroxylation of the methyl group of the substrates and subsequent Demethylation. Recent evidence has shown that these 2OG dioxygenases play vital roles in a variety of biological processes, including transcriptional regulation and gene expression. In this review, the structure and function of these dioxygenases in Histone and nucleic acid Demethylation will be discussed. Given the important roles of these 2OG dioxygenases, detailed analysis and comparison of the 2OG dioxygenases will guide the design of target-specific small-molecule chemical probes and inhibitors.
Yi Zhang - One of the best experts on this subject based on the ideXlab platform.
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screening of inhibitors against Histone Demethylation jumonji domain containing protein 3 by capillary electrophoresis
Journal of Chromatography A, 2020Co-Authors: Yi Zhang, Chunli Lou, Shanshan Qian, Jingwu KangAbstract:Abstract Jumonji domain-containing proteins (JMJDs) play an important role in the epigenetic regulation of gene expression. Aberrant regulation of Histone modification has been observed in the progression of a variety of diseases, such as neurological disorders and cancer. Therefore, discovery of selective modulators of JMJDs is very attractive in new drug discovery. Herein, a simple capillary electrophoresis (CE) method was developed for screening of inhibitors against JMJD3. A known JMJD3 inhibitor GSK-J1, 5-carboxyfluorescein labeled substrate peptide with an amino acid sequence of KAPRKQLATKAARK(me3)SAPATGG (truncated from Histone H3), as well as a small chemical library composed of 37 purified natural compounds and 30 natural extracts were used for method development and validation. The separation of substrate from its demethylated product was achieved by addition of polycation hexadimethrine bromide (HDB) in the running buffer. The enzyme activity was thus assayed accurately through separating the demethylated product from the substrate and then measuring the peak area of the product. The enzyme inhibition can be read out by comparing the peak area of the demethylated product obtained in the present of inhibitors and that of the negative control in the absence of any inhibitor. The merit of the method is proved by discovering two new JMJD3 inhibitors: salvianic acid A and puerarin 6′’-O-xyloside.
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jmjc domain containing proteins and Histone Demethylation
Nature Reviews Genetics, 2006Co-Authors: Robert J. Klose, Eric M. Kallin, Yi ZhangAbstract:Histone methylation has important roles in regulating gene expression and forms part of the epigenetic memory system that regulates cell fate and identity. Enzymes that directly remove methyl marks from Histones have recently been identified, revealing a new level of plasticity within this epigenetic modification system. Here we analyse the evolutionary relationship between Jumonji C (JmjC)-domain-containing proteins and discuss their cellular functions in relation to their potential enzymatic activities.
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JmjC-domain-containing proteins and Histone Demethylation
Nature Reviews Genetics, 2006Co-Authors: Robert J. Klose, Eric M. Kallin, Yi ZhangAbstract:Chromatin modifications affect many aspects of epigenetic inheritance and cell biology. The authors focus on evolutionary relationships among proteins containing the Jumonji C domain — the largest class of Histone demethylases — and discuss their functions in relation to potential enzymatic activities. Modification of Histone molecules within chromatin has a profound effect on genome structure and function. More specifically, methylation of Histone lysine residues is involved in regulating transcription, epigenetic inheritance and controlling cell fate. The recent identification of Histone demethylase enzymes has demonstrated that Histone methylation is a dynamic and reversible process, in contrast to the long-held opinion that this was a static modification. The Jumonji C (JmjC) domain can demethylate Histones by an oxidative mechanism requiring Fe(II) and alpha-ketoglutarate (αKG) as cofactors, in addition to carrying out protein hydroxylation reactions. Phylogenetic categorization based on JmjC-domain homology and protein domain architecture shows seven distinct JmjC-protein groupings. So far, three of these groupings encompass site-specific Histone demethylases, with the enzymatic activity of the remaining groups remaining unknown. Many of the uncharacterized JmjC-protein family members contain residues within the enzyme cofactor-binding sites which are compatible with enzymatic activity, indicating that additional JmjC proteins will probably have roles in Histone Demethylation and chromatin metabolism. Several JmjC-domain-containing proteins have been functionally implicated in inherited disease and cancer, indicating that these enzymes have important roles in cellular homeostasis and might be suitable targets for therapeutic intervention. Histone methylation has important roles in regulating gene expression and forms part of the epigenetic memory system that regulates cell fate and identity. Enzymes that directly remove methyl marks from Histones have recently been identified, revealing a new level of plasticity within this epigenetic modification system. Here we analyse the evolutionary relationship between Jumonji C (JmjC)-domain-containing proteins and discuss their cellular functions in relation to their potential enzymatic activities.
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jhdm2a a jmjc containing h3k9 demethylase facilitates transcription activation by androgen receptor
Cell, 2006Co-Authors: Kenichi Yamane, Yu Ichi Tsukada, Paul Tempst, Charalambos Toumazou, Hediye Erdjumentbromage, Jiemin Wong, Yi ZhangAbstract:Summary Covalent modification of Histones plays an important role in regulating chromatin dynamics and transcription. Histone methylation was thought to be an irreversible modification until recently. Using a biochemical assay coupled with chromatography, we have purified a JmjC domain-containing protein, JHDM2A, which specifically demethylates mono- and dimethyl-H3K9. Similar to JHDM1, JHDM2A-mediated Histone Demethylation requires cofactors Fe(II) and α-ketoglutarate. Mutational studies indicate that a JmjC domain and a zinc finger present in JHDM2A are required for its enzymatic activity. Overexpression of JHDM2A greatly reduced the H3K9 methylation level in vivo. Knockdown of JHDM2A results in an increase in the dimethyl-K9 levels at the promoter region of a subset of genes concomitant with decrease in their expression. Finally, JHDM2A exhibits hormone-dependent recruitment to androgen-receptor target genes, resulting in H3K9 Demethylation and transcriptional activation. Thus, our work identifies a Histone demethylase and links its function to hormone-dependent transcriptional activation.
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Histone Demethylation by a family of JmjC domain-containing proteins
Nature, 2006Co-Authors: Yu Ichi Tsukada, Maria E. Warren, Hediye Erdjument-bromage, Jia Fang, Christoph H Borchers, Paul Tempst, Yi ZhangAbstract:Covalent modification of Histones has an important role in regulating chromatin dynamics and transcription. Whereas most covalent Histone modifications are reversible, until recently it was unknown whether methyl groups could be actively removed from Histones. Using a biochemical assay coupled with chromatography, we have purified a novel JmjC domain-containing protein, JHDM1 (JmjC domain-containing Histone demethylase 1), that specifically demethylates Histone H3 at lysine 36 (H3-K36). In the presence of Fe(ii) and alpha-ketoglutarate, JHDM1 demethylates H3-methyl-K36 and generates formaldehyde and succinate. Overexpression of JHDM1 reduced the level of dimethyl-H3-K36 (H3K36me2) in vivo. The demethylase activity of the JmjC domain-containing proteins is conserved, as a JHDM1 homologue in Saccharomyces cerevisiae also has H3-K36 demethylase activity. Thus, we identify the JmjC domain as a novel demethylase signature motif and uncover a protein Demethylation mechanism that is conserved from yeast to human.
Cheryl H. Arrowsmith - One of the best experts on this subject based on the ideXlab platform.
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structure and function of dioxygenases in Histone Demethylation and dna rna Demethylation
IUCrJ, 2014Co-Authors: Cheng Dong, Jinrong Min, Heng Zhang, Cheryl H. ArrowsmithAbstract:Iron(II) and 2-oxoglutarate (2OG)-dependent dioxygenases involved in Histone and DNA/RNA Demethylation convert the cosubstrate 2OG and oxygen to succinate and carbon dioxide, resulting in hydroxylation of the methyl group of the substrates and subsequent Demethylation. Recent evidence has shown that these 2OG dioxygenases play vital roles in a variety of biological processes, including transcriptional regulation and gene expression. In this review, the structure and function of these dioxygenases in Histone and nucleic acid Demethylation will be discussed. Given the important roles of these 2OG dioxygenases, detailed analysis and comparison of the 2OG dioxygenases will guide the design of target-specific small-molecule chemical probes and inhibitors.
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Structure and function of dioxygenases in Histone Demethylation and DNA/RNA Demethylation
IUCrJ, 2014Co-Authors: Cheng Dong, Heng Zhang, Cheryl H. Arrowsmith, Jinrong MinAbstract:Iron(II) and 2-oxoglutarate (2OG)-dependent dioxygenases involved in Histone and DNA/RNA Demethylation convert the cosubstrate 2OG and oxygen to succinate and carbon dioxide, resulting in hydroxylation of the methyl group of the substrates and subsequent Demethylation. Recent evidence has shown that these 2OG dioxygenases play vital roles in a variety of biological processes, including transcriptional regulation and gene expression. In this review, the structure and function of these dioxygenases in Histone and nucleic acid Demethylation will be discussed. Given the important roles of these 2OG dioxygenases, detailed analysis and comparison of the 2OG dioxygenases will guide the design of target-specific small-molecule chemical probes and inhibitors.
Cheng Dong - One of the best experts on this subject based on the ideXlab platform.
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structure and function of dioxygenases in Histone Demethylation and dna rna Demethylation
IUCrJ, 2014Co-Authors: Cheng Dong, Jinrong Min, Heng Zhang, Cheryl H. ArrowsmithAbstract:Iron(II) and 2-oxoglutarate (2OG)-dependent dioxygenases involved in Histone and DNA/RNA Demethylation convert the cosubstrate 2OG and oxygen to succinate and carbon dioxide, resulting in hydroxylation of the methyl group of the substrates and subsequent Demethylation. Recent evidence has shown that these 2OG dioxygenases play vital roles in a variety of biological processes, including transcriptional regulation and gene expression. In this review, the structure and function of these dioxygenases in Histone and nucleic acid Demethylation will be discussed. Given the important roles of these 2OG dioxygenases, detailed analysis and comparison of the 2OG dioxygenases will guide the design of target-specific small-molecule chemical probes and inhibitors.
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Structure and function of dioxygenases in Histone Demethylation and DNA/RNA Demethylation
IUCrJ, 2014Co-Authors: Cheng Dong, Heng Zhang, Cheryl H. Arrowsmith, Jinrong MinAbstract:Iron(II) and 2-oxoglutarate (2OG)-dependent dioxygenases involved in Histone and DNA/RNA Demethylation convert the cosubstrate 2OG and oxygen to succinate and carbon dioxide, resulting in hydroxylation of the methyl group of the substrates and subsequent Demethylation. Recent evidence has shown that these 2OG dioxygenases play vital roles in a variety of biological processes, including transcriptional regulation and gene expression. In this review, the structure and function of these dioxygenases in Histone and nucleic acid Demethylation will be discussed. Given the important roles of these 2OG dioxygenases, detailed analysis and comparison of the 2OG dioxygenases will guide the design of target-specific small-molecule chemical probes and inhibitors.
Zu-hua Gao - One of the best experts on this subject based on the ideXlab platform.
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Correction: CXCR7/CXCR4 heterodimer-induced Histone Demethylation: a new mechanism of colorectal tumorigenesis.
Oncogene, 2019Co-Authors: Zhi-yu Song, Feng Wang, Shu-xiang Cui, Zu-hua GaoAbstract:A correction to this paper has been published and can be accessed via a link at the top of the paper.
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cxcr7 cxcr4 heterodimer induced Histone Demethylation a new mechanism of colorectal tumorigenesis
Oncogene, 2019Co-Authors: Zhi-yu Song, Feng Wang, Shu-xiang Cui, Zu-hua GaoAbstract:Both chemokine receptors (CXCRs) 7 and 4 can facilitate immune cell migration and mediate a vast array of physiological and pathological events. Herein we report, in both human and animal studies, that these two CXCRs can form heterodimers in vivo and promote colorectal tumorigenesis through Histone Demethylation. Compared with adjacent non-neoplastic tissue, human colorectal cancer (CRC) tissue showed a significant higher expression of CXCR4 and CXCR7, which was colocalized in the cancer cell epithelium. The CXCR/CXCR4 heterodimerization was associated with increased Histone demethylase JMJD2A. Villin-CXCR7-CXCR4 transgenic mice demonstrated a greater degree of exacerbated colitis and tumorigenesis than villin-CXCR7 and villin-CXCR4 mice. The CXCR7/CXCR4 heterodimerization also promoted APC mutation-driven colorectal tumorigenesis in APCMin/+/villin-CXCR7-CXCR4 mice. Further analysis showed that the CXCR7/CXCR4 heterodimer induced nuclear βarr1 recruitment and Histone demethylase JMJD2A, leading to Histone Demethylation and resulting in transcription of inflammatory factors and oncogenes. This study uncovered a novel mechanism of colorectal tumorigenesis through the CXCR7/CXCR4 heterodimer-induced Histone Demethylation. Inhibition of CXCR7/CXCR4 heterodimer-induced Histone Demethylation could be an effective strategy for the prevention and treatment of colorectal cancer.
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CXCR7/CXCR4 heterodimer-induced Histone Demethylation: a new mechanism of colorectal tumorigenesis.
Oncogene, 2018Co-Authors: Zhi-yu Song, Feng Wang, Shu-xiang Cui, Zu-hua GaoAbstract:Both chemokine receptors (CXCRs) 7 and 4 can facilitate immune cell migration and mediate a vast array of physiological and pathological events. Herein we report, in both human and animal studies, that these two CXCRs can form heterodimers in vivo and promote colorectal tumorigenesis through Histone Demethylation. Compared with adjacent non-neoplastic tissue, human colorectal cancer (CRC) tissue showed a significant higher expression of CXCR4 and CXCR7, which was colocalized in the cancer cell epithelium. The CXCR/CXCR4 heterodimerization was associated with increased Histone demethylase JMJD2A. Villin-CXCR7-CXCR4 transgenic mice demonstrated a greater degree of exacerbated colitis and tumorigenesis than villin-CXCR7 and villin-CXCR4 mice. The CXCR7/CXCR4 heterodimerization also promoted APC mutation-driven colorectal tumorigenesis in APCMin/+/villin-CXCR7-CXCR4 mice. Further analysis showed that the CXCR7/CXCR4 heterodimer induced nuclear βarr1 recruitment and Histone demethylase JMJD2A, leading to Histone Demethylation and resulting in transcription of inflammatory factors and oncogenes. This study uncovered a novel mechanism of colorectal tumorigenesis through the CXCR7/CXCR4 heterodimer-induced Histone Demethylation. Inhibition of CXCR7/CXCR4 heterodimer-induced Histone Demethylation could be an effective strategy for the prevention and treatment of colorectal cancer.