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Yu Zhang - One of the best experts on this subject based on the ideXlab platform.

  • histone demethylase jmjd2b coordinates h3k4 h3k9 methylation and promotes hormonally responsive breast carcinogenesis
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Qian Li, Chenghao Xuan, Xia Yi, Wenhua Yu, Xiaohan Yang, Yanyan Li, Jing Liang, Yu Zhang, Yongfeng Shang
    Abstract:

    It is well-documented that the methylation of histone H3 lysine 4 (H3K4) and of H3K9 are mutually exclusive, an epigenetic phenomenon conserved from yeast to humans. How this opposed methylation modification is accomplished and coordinated in mammalian cells is poorly understood. Here we report that the H3K9 trimethyl demethylase JMJD2B is an integral component of the H3K4-specific methyltransferase, the mixed-lineage leukemia (MLL) 2 complex. We show that the JMJD2B/MLL2 complex is copurified with estrogen receptor α (ERα) and is required for ERα-regulated transcription. We demonstrate that H3K9 demethylation and H3K4 methylation are coordinated in ERα-activated transcription such that H3K9 demethylation is a prerequisite for H3K4 methylation. Significantly, depletion of JMJD2B impairs the estrogen-induced G1/S transition of the cell cycle in vitro and inhibits breast tumorigenesis in vivo. Interestingly, JMJD2B itself is an ERα target gene, and forms a feed-forward regulatory loop in regulation of the hormone response. Our results provide a molecular basis for the coordinated H3K4 methylation/H3K9 demethylation in transcription activation, link the trimethyl demethylase JMJD2B to euchromatin functions, and provide a mechanism for JMJD2B in breast carcinogenesis.

  • Histone demethylase JMJD2B coordinates H3K4/H3K9 methylation and promotes hormonally responsive breast carcinogenesis
    proceedings of the national academy of sciences of the united states of america, 2011
    Co-Authors: Shi Lei, Sun Luyang, Li Qian, Liang Jing, Yu Wenhua, Yi Xia, Yang Xiaohan, Li Yanyan, Han Xiao, Yu Zhang
    Abstract:

    It is well-documented that the methylation of histone H3 lysine 4 (H3K4) and of H3K9 are mutually exclusive, an epigenetic phenomenon conserved from yeast to humans. How this opposed methylation modification is accomplished and coordinated in mammalian cells is poorly understood. Here we report that the H3K9 trimethyl demethylase JMJD2B is an integral component of the H3K4-specific methyltransferase, the mixed-lineage leukemia (MLL) 2 complex. We show that the JMJD2B/MLL2 complex is copurified with estrogen receptor alpha (ER alpha) and is required for ER alpha-regulated transcription. We demonstrate that H3K9 demethylation and H3K4 methylation are coordinated in ER alpha-activated transcription such that H3K9 demethylation is a prerequisite for H3K4 methylation. Significantly, depletion of JMJD2B impairs the estrogen-induced G(1)/S transition of the cell cycle in vitro and inhibits breast tumorigenesis in vivo. Interestingly, JMJD2B itself is an ER alpha target gene, and forms a feed-forward regulatory loop in regulation of the hormone response. Our results provide a molecular basis for the coordinated H3K4 methylation/H3K9 demethylation in transcription activation, link the trimethyl demethylase JMJD2B to euchromatin functions, and provide a mechanism for JMJD2B in breast carcinogenesis.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000290203100054&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Multidisciplinary SciencesSCI(E)PubMed93ARTICLE187541-754610

  • the histone demethylase jmjd2c is stage specifically expressed in preimplantation mouse embryos and is required for embryonic development
    Biology of Reproduction, 2010
    Co-Authors: Jianle Wang, Yu Zhang, Qingyuan Sun, Zhiming Han, Miao Zhang, Zhaohui Kou, Dayuan Chen, Shaorong Gao
    Abstract:

    Epigenetic modifications play a pivotal role in embryonic development by dynamically regulating DNA methylation and chromatin modifications. Although recent studies have shown that core histone methylation is reversible, very few studies have investigated the functions of the newly discovered histone demethylases during embryonic development. In the present study, we investigated the expression characteristics and function of JMJD2C, a histone demethylase that belongs to the JmjC-domain-containing histone demethylases, during preimplantation embryonic development of the mouse. We found that JMJD2C is stage-specifically expressed during preimplantation development, with the highest activity being observed from the two-cell to the eight-cell stage. Depletion of JMJD2C in metaphase II oocytes followed by parthenogenetic activation causes a developmental arrest before the blastocyst stage. Moreover, consistent with a previous finding in embryonic stem (ES) cells, depletion of JMJD2C causes a significant down-regulation of the pluripotency gene Nanog in embryos. However, contrary to a previous report in ES cells, we observed that other pluripotency genes, Pou5f1 and Sox2, are also significantly down-regulated in JMJD2C-depleted embryos. Furthermore, the depletion of JMJD2C in early embryos also caused significant down-regulation of the Myc and Klf4 genes, which are associated with cell proliferation. Our data suggest that the deregulation of these critical genes synergistically causes the developmental defects observed in JMJD2C-depleted embryos.

Yi Zhang - One of the best experts on this subject based on the ideXlab platform.

  • abstract 2985 the histone demethylase jmjd1a induces neuroblastoma cell migration and invasion
    Cancer Research, 2013
    Co-Authors: Dora Ling, Takayoshi Suzuki, Andrew E Tee, Charlotte Nelson, Bernard Atmadibrata, Pei Y Liu, Eddy Pasquier, Glenn M Marshall, Yi Zhang, Tao Liu
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Patients with neuroblastoma due to N-Myc oncogene-amplification die of tumour metastasis. However, little is known about how N-Myc induces cell migration, invasion and metastasis. The histone demethylase JMJD1A activates target gene transcription by demethylating lysine 9 residues of histone H3 (H3K9). Here we demonstrated that N-Myc up-regulated the expression of JMJD1A in N-Myc oncogene-amplified human neuroblastoma cells by directly binding to JMJD1A gene promoter. Affymetrix gene array studies revealed that the gene most significantly up-regulated by JMJD1A was the long intergenic noncoding RNA Metastasis-associated Lung Adenocarcinoma Transcript 1 (MALAT1). Consistent with this finding, chromatin immunoprecipitation showed that JMJD1A bound to MALAT1 gene promoter. Importantly, JMJD1A siRNAs, MALAT1 siRNAs and small molecule JMJD1A inhibitors impeded neuroblastoma cell migration and invasion. Taken together, our data identify a novel pathway through which N-Myc causes neuroblastoma cell migration, invasion and potentially metastasis. Citation Format: Dora Ling, Andrew Tee, Charlotte Nelson, Ning Xu, Bernard Atmadibrata, Pei Y. Liu, Eddy Pasquier, Glenn M. Marshall, Takayoshi Suzuki, Yi Zhang, Tao Liu. The histone demethylase JMJD1A induces neuroblastoma cell migration and invasion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2985. doi:10.1158/1538-7445.AM2013-2985

  • nickel ions inhibit histone demethylase jmjd1a and dna repair enzyme abh2 by replacing the ferrous iron in the catalytic centers
    Journal of Biological Chemistry, 2010
    Co-Authors: Haobin Chen, Yi Zhang, Nitai Giri, Ronghe Zhang, Kenichi Yamane, Michael J Maroney, Max Costa
    Abstract:

    Iron- and 2-oxoglutarate-dependent dioxygenases are a diverse family of non-heme iron enzymes that catalyze various important oxidations in cells. A key structural motif of these dioxygenases is a facial triad of 2-histidines-1-carboxylate that coordinates the Fe(II) at the catalytic site. Using histone demethylase JMJD1A and DNA repair enzyme ABH2 as examples, we show that this family of dioxygenases is highly sensitive to inhibition by carcinogenic nickel ions. We find that, with iron, the 50% inhibitory concentrations of nickel (IC50 [Ni(II)]) are 25 μm for JMJD1A and 7.5 μm for ABH2. Without iron, JMJD1A is 10 times more sensitive to nickel inhibition with an IC50 [Ni(II)] of 2.5 μm, and approximately one molecule of Ni(II) inhibits one molecule of JMJD1A, suggesting that nickel causes inhibition by replacing the iron. Furthermore, nickel-bound JMJD1A is not reactivated by excessive iron even up to a 2 mm concentration. Using x-ray absorption spectroscopy, we demonstrate that nickel binds to the same site in ABH2 as iron, and replacement of the iron by nickel does not prevent the binding of the cofactor 2-oxoglutarate. Finally, we show that nickel ions target and inhibit JMJD1A in intact cells, and disruption of the iron-binding site decreases binding of nickel ions to ABH2 in intact cells. Together, our results reveal that the members of this dioxygenase family are specific targets for nickel ions in cells. Inhibition of these dioxygenases by nickel is likely to have widespread impacts on cells (e.g. impaired epigenetic programs and DNA repair) and may eventually lead to cancer development.

  • the transcriptional repressor jhdm3a demethylates trimethyl histone h3 lysine 9 and lysine 36
    Nature, 2006
    Co-Authors: Yi Zhang, Hediye Erdjumentbromage, Kenichi Yamane, Robert J Klose, Dianzheng Zhang, Paul Tempst, Jiemin Wong
    Abstract:

    One of two papers in this issue that identifies enzymes capable of demethylating a tri-methyl group from Lys 9 of histone H3 — a mark required for the establishment of heterochromatin and previously considered to be stable. JHDM3A, a member of the JMJD2 enzyme family, can disrupt heterochromatin structure when overexpressed and may function in euchromatin to regulate transcription.

  • recognition of histone h3 lysine 4 methylation by the double tudor domain of JMJD2A
    Science, 2006
    Co-Authors: Ying Huang, Jia Fang, Mark T Edford, Yi Zhang
    Abstract:

    Biological responses to histone methylation critically depend on the faithful readout and transduction of the methyl-lysine signal by "effector" proteins, yet our understanding of methyl-lysine recognition has so far been limited to the study of histone binding by chromodomain and WD40-repeat proteins. The double tudor domain of JMJD2A, a Jmjc domain-containing histone demethylase, binds methylated histone H3-K4 and H4-K20. We found that the double tudor domain has an interdigitated structure, and the unusual fold is required for its ability to bind methylated histone tails. The cocrystal structure of the JMJD2A double tudor domain with a trimethylated H3-K4 peptide reveals that the trimethyl-K4 is bound in a cage of three aromatic residues, two of which are from the tudor-2 motif, whereas the binding specificity is determined by side-chain interactions involving amino acids from the tudor-1 motif. Our study provides mechanistic insights into recognition of methylated histone tails by tudor domains and reveals the structural intricacy of methyl-lysine recognition by two closely spaced effector domains.

Ralf Janknecht - One of the best experts on this subject based on the ideXlab platform.

  • cooperation between ets variant 2 and jumonji domain containing 2 histone demethylases
    Molecular Medicine Reports, 2018
    Co-Authors: Gene Moon, Sook Shin, Bin Zhang, Ralf Janknecht
    Abstract:

    The E26 transformation-specific (ETS) variant 2 (ETV2) protein, also designated as ETS-related 71, is a member of the ETS transcription factor family and is essential for blood and vascular development in the embryo. The role of ETV2 in cancer has not yet been investigated. In the present study, the expression of ETV2 mRNA was identified in a variety of tumor types, including prostate carcinoma. In addition, ETV2 gene amplification was identified in several types of cancer, suggesting that ETV2 plays an oncogenic role in tumorigenesis. It was demonstrated that ETV2 forms complexes with two histone demethylases: Jumonji domain‑containing (JMJD)2A and JMJD2D; JMJD2A has been previously reported as a driver of prostate cancer development. In the present study, it was reported that ETV2 exhibited the potential to stimulate the promoters of matrix metalloproteinases (MMPs), including MMP1 and MMP7, within LNCaP prostate cancer cells. JMJD2A and JMJD2D could synergize with ETV2 to activate the MMP1 promoter, whereas only JMJD2A stimulated the MMP7 promoter in cooperation with ETV2. Furthermore, ETV2 expression was positively associated with JMJD2A and JMJD2D mRNA levels in neuroendocrine prostate tumors, in which an ETV2 gene amplification rate of 17.8% was identified. Collectively, the results of the present study indicated that ETV2, JMJD2A and JMJD2D may jointly promote tumorigenesis, particularly neuroendocrine prostate tumors. In addition, the interaction with the JMJD2A and JMJD2D epigenetic regulators may be important in the ability of ETV2 to reprogram cells, modulate normal and cancer stem cells, and affect spermatogenesis.

  • regulation of tumor suppressor p53 and hct116 cell physiology by histone demethylase jmjd2d kdm4d
    PLOS ONE, 2012
    Co-Authors: Tae Dong Kim, Sook Shin, Ralf Janknecht
    Abstract:

    JMJD2D, also known as KDM4D, is a histone demethylase that removes methyl moieties from lysine 9 on histone 3 and from lysine 26 on histone 1.4. Here, we demonstrate that JMJD2D forms a complex with the p53 tumor suppressor in vivo and interacts with the DNA binding domain of p53 in vitro. A luciferase reporter plasmid driven by the promoter of p21, a cell cycle inhibitor and prominent target gene of p53, was synergistically activated by p53 and JMJD2D, which was dependent on JMJD2D catalytic activity. Likewise, overexpression of JMJD2D induced p21 expression in U2OS osteosarcoma cells in the absence and presence of adriamycin, an agent that induces DNA damage. Furthermore, downregulation of JMJD2D inhibited cell proliferation in wild-type and even more so in p53−/− HCT116 colon cancer cells, suggesting that JMJD2D is a pro-proliferative molecule. JMJD2D depletion also induced more strongly apoptosis in p53−/− compared to wild-type HCT116 cells. Collectively, our results demonstrate that JMJD2D can stimulate cell proliferation and survival, suggesting that its inhibition may be helpful in the fight against cancer. Furthermore, our data imply that activation of p53 may represent a mechanism by which the pro-oncogenic functions of JMJD2D become dampened.

  • synthesis and activity of n oxalylglycine and its derivatives as jumonji c domain containing histone lysine demethylase inhibitors
    Bioorganic & Medicinal Chemistry Letters, 2009
    Co-Authors: Shohei Hamada, Takayoshi Suzuki, Yukihiro Itoh, Hiroki Tsumoto, Hidehiko Nakagawa, Ralf Janknecht, Naoki Miyata
    Abstract:

    N-Oxalylglycine (NOG) derivatives were synthesized, and their inhibitory effect on histone lysine demethylase activity was evaluated. NOG and compound 1 inhibited histone lysine demethylases JMJD2A, 2C and 2D in enzyme assays, and their dimethyl ester prodrugs DMOG and 21 exerted histone lysine methylating activity in cellular assays.

  • diversity within the jmjd2 histone demethylase family
    Biochemical and Biophysical Research Communications, 2007
    Co-Authors: Sook Shin, Ralf Janknecht
    Abstract:

    JMJD2A-D belong to the JmjC domain-containing family of histone demethylases. JMJD2D is the most structurally divergent JMJD2 protein as it lacks the PHD and Tudor domains present in JMJD2A-C. Here, we systematically analyzed the histone demethylase specificity of JMJD2 proteins in vivo. We found that JMJD2A and C demethylate tri- and dimethylated H3K9 and H3K36, whereas JMJD2D demethylates tri-, di-, and monomethylated H3K9. Enzymatic activity requires the N-terminal JmjN domain. It also contributes to efficient nuclear localization together with the PHD and Tudor domains of JMJD2A and C. Furthermore, JMJD2 proteins form homomers, and JMJD2A and C, but not JMJD2D, can also heteromerize. Finally, we show that JMJD2 proteins promoter-specifically repress or activate gene transcription. Altogether, our results reveal novel properties of and functional differences between JMJD2 proteins that may therefore have different effects on chromatin structure.

Hitoshi Okada - One of the best experts on this subject based on the ideXlab platform.

  • erratum the histone demethylase jmjd2b regulates endothelial to mesenchymal transition proceedings of the national academy of sciences of the united states of america 2020 117 4180 4187 doi 10 1073 pnas 1913481117
    Proceedings of the National Academy of Sciences of the United States of America, 2020
    Co-Authors: Simone F Glaser, Hitoshi Okada, Andreas W Heumuller, Lukas Tombor, Patrick Hofmann, Marion Muhlyreinholz, Ariane Fischer, Stefan Gunther, Karoline E Kokot, David Hassel
    Abstract:

    Correction for “The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition,” by Simone F. Glaser, Andreas W. Heumuller, Lukas Tombor, Patrick Hofmann, Marion Muhly-Reinholz, Ariane Fischer, Stefan Gunther, Karoline E. Kokot, David Hassel, Sandeep Kumar, Hanjoong Jo, Reinier A. Boon, Wesley Abplanalp, David John, Jes-Niels Boeckel, and Stefanie Dimmeler, which was first published February 7, 2020; 10.1073/pnas.1913481117 (Proc. Natl. Acad. Sci. U.S.A. 117, 4180-4187). The authors note that Hitoshi Okada should be added to the author list between Karoline E. Kokot and David Hassel. Hitoshi Okada should be credited with providing mice. The corrected author line, affiliation line, and author contributions appear below. The online version has been corrected.

  • histone demethylase jmjd2b functions as a co factor of estrogen receptor in breast cancer proliferation and mammary gland development
    PLOS ONE, 2011
    Co-Authors: Masahito Kawazu, Kayoko Saso, Kit I Tong, Tracy Mcquire, Kouichiro Goto, Andrew Wakeham, Makoto Miyagishi, Hitoshi Okada
    Abstract:

    Estrogen is a key regulator of normal function of female reproductive system and plays a pivotal role in the development and progression of breast cancer. Here, we demonstrate that JMJD2B (also known as KDM4B) constitutes a key component of the estrogen signaling pathway. JMJD2B is expressed in a high proportion of human breast tumors, and that expression levels significantly correlate with estrogen receptor (ER) positivity. In addition, 17-beta-estradiol (E2) induces JMJD2B expression in an ERα dependent manner. JMJD2B interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex. JMJD2B is recruited to ERα target sites, demethylates H3K9me3 and facilitates transcription of ER responsive genes including MYB, MYC and CCND1. As a consequence, knockdown of JMJD2B severely impairs estrogen-induced cell proliferation and the tumor formation capacity of breast cancer cells. Furthermore, Jmjd2b-deletion in mammary epithelial cells exhibits delayed mammary gland development in female mice. Taken together, these findings suggest an essential role for JMJD2B in the estrogen signaling, and identify JMJD2B as a potential therapeutic target in breast cancer.

Yongfeng Shang - One of the best experts on this subject based on the ideXlab platform.

  • histone demethylase jmjd2b coordinates h3k4 h3k9 methylation and promotes hormonally responsive breast carcinogenesis
    Proceedings of the National Academy of Sciences of the United States of America, 2011
    Co-Authors: Qian Li, Chenghao Xuan, Xia Yi, Wenhua Yu, Xiaohan Yang, Yanyan Li, Jing Liang, Yu Zhang, Yongfeng Shang
    Abstract:

    It is well-documented that the methylation of histone H3 lysine 4 (H3K4) and of H3K9 are mutually exclusive, an epigenetic phenomenon conserved from yeast to humans. How this opposed methylation modification is accomplished and coordinated in mammalian cells is poorly understood. Here we report that the H3K9 trimethyl demethylase JMJD2B is an integral component of the H3K4-specific methyltransferase, the mixed-lineage leukemia (MLL) 2 complex. We show that the JMJD2B/MLL2 complex is copurified with estrogen receptor α (ERα) and is required for ERα-regulated transcription. We demonstrate that H3K9 demethylation and H3K4 methylation are coordinated in ERα-activated transcription such that H3K9 demethylation is a prerequisite for H3K4 methylation. Significantly, depletion of JMJD2B impairs the estrogen-induced G1/S transition of the cell cycle in vitro and inhibits breast tumorigenesis in vivo. Interestingly, JMJD2B itself is an ERα target gene, and forms a feed-forward regulatory loop in regulation of the hormone response. Our results provide a molecular basis for the coordinated H3K4 methylation/H3K9 demethylation in transcription activation, link the trimethyl demethylase JMJD2B to euchromatin functions, and provide a mechanism for JMJD2B in breast carcinogenesis.