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Rute A Tomaz, Jennifer L Harman, Donja Karimlou, Lauren Weavers, Lauriane Fritsch, Tony Bou-Kheir, Emma Bell, Ignacio Del Valle Torres, Kathy K Niakan, Cynthia Fisher, Onkar Joshi, Hendrik G Stunnenberg, Edward Curry, Slimane Ait-Si-Ali, Helle F Jørgensen, Véronique Azuara
Jmjd2/Kdm4 H3K9-demethylases cooperate in promoting mouse embryonic stem cell (ESC) identity. However, little is known about their importance at the exit of ESC pluripotency. Here, we uncover that Jmjd2c facilitates this process by stabilizing the assembly of Mediator-Cohesin complexes at lineage-specific enhancers. Functionally, we show that Jmjd2c is required in ESCs to initiate appropriate gene expression programs upon somatic multi-lineage differentiation. In the absence of Jmjd2c, differentiation is stalled at an early post-implantation epiblast-like stage, while Jmjd2c-knockout ESCs remain capable of forming extra-embryonic endoderm derivatives...
January 13, 2017: Development
Rebecca L Hancock, Norma Masson, Kate Dunne, Emily Flashman, Akane Kawamura
The JmjC-histone lysine demethylases (KDMs) are epigenetic regulators involved in the removal of methyl groups from post-translationally modified lysyl residues within the histone tails, modulating gene transcription. These enzymes require molecular oxygen for catalytic activity and, as 2-oxoglutarate (2OG) dependent oxygenases, are related to the cellular oxygen sensing HIF hydroxylases PHD2 and FIH. Recent studies have indicated that the activity of some KDMs, including the pseudogene-encoded KDM4E, may be sensitive to changing oxygen concentrations...
January 4, 2017: ACS Chemical Biology
Salil Saurav Pathak, Swati Maitra, Sumana Chakravarty, Arvind Kumar
Major depressive disorder (MDD) is debilitating mental illness and is one of the leading contributors to global burden of disease, but unfortunately newer and better drugs are not forthcoming. The reason is lack of complete understanding of molecular mechanisms underlying the development of this disorder. Recent research shows dysregulation in epigenetic regulatory mechanisms, particularly the transcriptionally repressive di- and tri-methylation of histone 3 lysine 9 (H3K9me2/me3) in nucleus accumbens (NAc), a critical region of the reward pathway involved in the development of anhedonia, the hallmark of depression...
October 26, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Megan Breski, Debasis Dey, Sara Obringer, Babu Sudhamalla, Kabirul Islam
Oxidative C-H hydroxylation of methyl groups, followed by their removal from DNA, RNA or histones, is an epigenetic process critical to transcriptional reprogramming and cell fate determination. This reaction is catalyzed by Fe(II)-dependent dioxygenases using the essential metabolite 2-ketoglutarate (2KG) as a cofactor. Given that the human genome encodes for more than 60 2KG-dependent dioxygenases, assigning their individual functions remains a significant challenge. Here we describe a protein-ligand interface engineering approach to break the biochemical degeneracy of these enzymes...
October 6, 2016: Journal of the American Chemical Society
Sumana Chakravarty, Priya Jhelum, Unis Ahmad Bhat, Wenson D Rajan, Swati Maitra, Salil S Pathak, Anant B Patel, Arvind Kumar
Cerebral ischemic stroke is one of the leading causes of death and disability worldwide. Therapeutic interventions to minimize ischemia-induced neural damage are limited due to poor understanding of molecular mechanisms mediating complex pathophysiology in stroke. Recently, epigenetic mechanisms mostly histone lysine (K) acetylation and deacetylation have been implicated in ischemic brain damage and have expanded the dimensions of potential therapeutic intervention to the systemic/local administration of histone deacetylase inhibitors...
January 2017: Biochimica et Biophysica Acta
Hamid Bur, Kirsi-Maria Haapasaari, Taina Turpeenniemi-Hujanen, Outi Kuittinen, Päivi Auvinen, Katja Marin, Ylermi Soini, Peeter Karihtala
BACKGROUND: Epigenetic regulators, including Jumonji domain 2 (JMJD2/KDM4) proteins are involved in post-translational modification of histone demethylation and have a major role in carcinogenesis of many solid tumors. MATERIALS AND METHODS: We assessed immunohistochemically the expression of lysine (K)-specific demethylase 4 (KDM4)A, KDM4B and KDM4D in tumors from 91 patients of adriamycin, bleomycin, vinblastine, darcabazine (ABVD)-treated classical Hodgkin lymphoma...
2016: Anticancer Research
Angela Hayes, N Yi Mok, Manjuan Liu, Ching Thai, Alan T Henley, Butrus Atrash, Rachel M Lanigan, Jimmy Sejberg, Yann-Vaï Le Bihan, Vassilios Bavetsias, Julian Blagg, Florence I Raynaud
1.We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases. 2.Although exemplar compound 1 exhibited moderate clearance in mouse liver microsomes, it was highly cleared in vivo due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold and other C8-substituted derivatives. 3.We identified the C2-position as the oxidation site by LC-MS and (1)H-NMR and showed that C2-substituted derivatives are no longer AO substrates...
September 12, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Haijie Li, Xi Yang, Guihua Wang, Xiaolan Li, Deding Tao, Junbo Hu, Xuelai Luo
Histone methyltransferases and demethylases regulate transcription by altering the epigenetic marks on histones in tumorigenesis. Members of the histone lysine(K)-specific demethylase 4 (KDM4) family are dysregulated in several types of cancer. Here, we report a novel role for KDM4B in mitochondrial apoptosis. In this study, we demonstrate that KDM4B is overexpressed in colorectal cancer (CRC) tissues. Decreased expression of KDM4B significantly promoted apoptosis of CRC cell lines. Moreover, our data indicate that HAX1 is required for KDM4B-mediated mitochondrial apoptosis...
September 6, 2016: Oncotarget
Karl Agger, Satoru Miyagi, Marianne Terndrup Pedersen, Susanne M Kooistra, Jens Vilstrup Johansen, Kristian Helin
Acute myeloid leukemias (AMLs) with a rearrangement of the mixed-linage leukemia (MLL) gene are aggressive hematopoietic malignancies. Here, we explored the feasibility of using the H3K9- and H3K36-specific demethylases Jmjd2/Kdm4 as putative drug targets in MLL-AF9 translocated leukemia. Using Jmjd2a, Jmjd2b, and Jmjd2c conditional triple-knockout mice, we show that Jmjd2/Kdm4 activities are required for MLL-AF9 translocated AML in vivo and in vitro. We demonstrate that expression of the interleukin 3 receptor α (Il3ra also known as Cd123) subunit is dependent on Jmjd2/Kdm4 through a mechanism involving removal of H3K9me3 from the promoter of the Il3ra gene...
June 1, 2016: Genes & Development
Catrine Johansson, Srikannathasan Velupillai, Anthony Tumber, Aleksandra Szykowska, Edward S Hookway, Radoslaw P Nowak, Claire Strain-Damerell, Carina Gileadi, Martin Philpott, Nicola Burgess-Brown, Na Wu, Jola Kopec, Andrea Nuzzi, Holger Steuber, Ursula Egner, Volker Badock, Shonagh Munro, Nicholas B LaThangue, Sue Westaway, Jack Brown, Nick Athanasou, Rab Prinjha, Paul E Brennan, Udo Oppermann
Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe(2+)-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families...
July 2016: Nature Chemical Biology
Lindsey R Pack, Keith R Yamamoto, Danica Galonić Fujimori
Histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 9 trimethylation (H3K9me3) are epigenetic marks with opposing roles in transcription regulation. Whereas colocalization of these modifications is generally excluded in the genome, how this preclusion is established remains poorly understood. Lysine demethylase 4C (KDM4C), an H3K9me3 demethylase, localizes predominantly to H3K4me3-containing promoters through its hybrid tandem tudor domain (TTD) (1, 2), providing a model for how these modifications might be excluded...
March 18, 2016: Journal of Biological Chemistry
Magdalena Korczynska, Daniel D Le, Noah Younger, Elisabet Gregori-Puigjané, Anthony Tumber, Tobias Krojer, Srikannathasan Velupillai, Carina Gileadi, Radosław P Nowak, Eriko Iwasa, Samuel B Pollock, Idelisse Ortiz Torres, Udo Oppermann, Brian K Shoichet, Danica Galonić Fujimori
Development of tool molecules that inhibit Jumonji demethylases allows for the investigation of cancer-associated transcription. While scaffolds such as 2,4-pyridinedicarboxylic acid (2,4-PDCA) are potent inhibitors, they exhibit limited selectivity. To discover new inhibitors for the KDM4 demethylases, enzymes overexpressed in several cancers, we docked a library of 600,000 fragments into the high-resolution structure of KDM4A. Among the most interesting chemotypes were the 5-aminosalicylates, which docked in two distinct but overlapping orientations...
February 25, 2016: Journal of Medicinal Chemistry
Gareth W Langley, Anne Brinkø, Martin Münzel, Louise J Walport, Christopher J Schofield, Richard J Hopkinson
The dynamic post-translational modifications of histones play important roles in the regulation of transcription in animals. The demethylation of N(ε)-methyl lysine residues in the N-terminal tail of histone H3 is catalyzed by demethylases, of which the largest family is the ferrous iron and 2-oxoglutarate dependent demethylases (JmjC KDMs), which catalyze demethylation via initial hydroxylation of the N-methyl groups. We report studies on the conformational requirements of the JmjC KDM substrates using N-methylated lysine analogues prepared by metathesis reactions of suitably protected N-allylglycine...
March 18, 2016: ACS Chemical Biology
Lingling Duan, Ganesha Rai, Carlos Roggero, Qing-Jun Zhang, Qun Wei, Shi Hong Ma, Yunyun Zhou, John Santoyo, Elisabeth D Martinez, Guanghua Xiao, Ganesh V Raj, Ajit Jadhav, Anton Simeonov, David J Maloney, Josep Rizo, Jer-Tsong Hsieh, Zhi-Ping Liu
Histone lysine demethylase KDM4/JMJD2s are overexpressed in many human tumors including prostate cancer (PCa). KDM4s are co-activators of androgen receptor (AR) and are thus potential therapeutic targets. Yet to date few KDM4 inhibitors that have anti-prostate tumor activity in vivo have been developed. Here, we report the anti-tumor growth effect and molecular mechanisms of three novel KDM4 inhibitors (A1, I9, and B3). These inhibitors repressed the transcription of both AR and BMYB-regulated genes. Compound B3 is highly selective for a variety of cancer cell lines including PC3 cells that lack AR...
September 17, 2015: Chemistry & Biology
C C Thinnes, A Tumber, C Yapp, G Scozzafava, T Yeh, M C Chan, T A Tran, K Hsu, H Tarhonskaya, L J Walport, S E Wilkins, E D Martinez, S Müller, C W Pugh, P J Ratcliffe, P E Brennan, A Kawamura, C J Schofield
There is interest in developing potent, selective, and cell-permeable inhibitors of human ferrous iron and 2-oxoglutarate (2OG) oxygenases for use in functional and target validation studies. The 3-component Betti reaction enables efficient one-step C-7 functionalisation of modified 8-hydroxyquinolines (8HQs) to produce cell-active inhibitors of KDM4 histone demethylases and other 2OG oxygenases; the work exemplifies how a template-based metallo-enzyme inhibitor approach can be used to give biologically active compounds...
October 28, 2015: Chemical Communications: Chem Comm
Yong Huang, Donghong Chen, Chunlin Liu, Wenhui Shen, Ying Ruan
Histone modification regulates plant development events by epigenetically silencing or activating gene expression, and histone methylation is regulated by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). The JmjC domain proteins, an important KDM family, erase methyl marks (CH3-) from histones and play key roles in maintaining homeostasis of histone methylation in vivo. Here, we analyzed 169 JmjC domain proteins from whole genomes of plants ranging from green alga to higher plants together with 36 from two animals (fruit fly and human)...
February 2016: Molecular Genetics and Genomics: MGG
Qin Ye, Andreana Holowatyj, Jack Wu, Hui Liu, Lihong Zhang, Takayoshi Suzuki, Zeng-Quan Yang
The histone lysine demethylase KDM4 subfamily, comprised of four members (A, B, C, and D), play critical roles in controlling transcription, chromatin architecture and cellular differentiation. We previously demonstrated that KDM4C is significantly amplified and overexpressed in aggressive basal-like breast cancers and functions as a transforming oncogene. However, information regarding the genomic and transcriptomic alterations of the KDM4 subfamily in different subtypes of breast cancer remains largely incomplete...
2015: American Journal of Cancer Research
Shengzhan Qian, Yingxiang Wang, Hong Ma, Liangsheng Zhang
Histone modifications, such as methylation and demethylation, are crucial mechanisms altering chromatin structure and gene expression. Recent biochemical and molecular studies have uncovered a group of histone demethylases called Jumonji C (JmjC) domain proteins. However, their evolutionary history and patterns have not been examined systematically. Here, we report extensive analyses of eukaryotic JmjC genes and define 14 subfamilies, including the Lysine-Specific Demethylase3 (KDM3), KDM5, JMJD6, Putative-Lysine-Specific Demethylase11 (PKDM11), and PKDM13 subfamilies, shared by plants, animals, and fungi...
August 2015: Plant Physiology
Samah W Awwad, Nabieh Ayoub
The KDM4 family of lysine demethylases consists of five members, KDM4A, -B and -C that demethylate H3K9me2/3 and H3K36me2/3 marks, while KDM4D and -E demethylate only H3K9me2/3. Recent studies implicated KDM4 proteins in regulating genomic instability and carcinogenesis. Here, we describe a previously unrecognized pathway by which hyperactivity of KDM4 demethylases promotes genomic instability. We show that overexpression of KDM4A-C, but not KDM4D, disrupts MSH6 foci formation during S phase by demethylating its binding site, H3K36me3...
2015: Biology Open
Agnieszka Gacek-Matthews, Luke M Noble, Clemens Gruber, Harald Berger, Michael Sulyok, Ana T Marcos, Joseph Strauss, Alex Andrianopoulos
Aspergillus nidulans kdmA encodes a member of the KDM4 family of jumonji histone demethylase proteins, highly similar to metazoan orthologues both within functional domains and in domain architecture. This family of proteins exhibits demethylase activity towards lysines 9 and 36 of histone H3 and plays a prominent role in gene expression and chromosome structure in many species. Mass spectrometry mapping of A. nidulans histones revealed that around 3% of bulk histone H3 carried trimethylated H3K9 (H3K9me3) but more than 90% of histones carried either H3K36me2 or H3K36me3...
May 2015: Molecular Microbiology
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