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Histone demethylases

Zhaojun Cao, Yue Yin, Xuan Sun, Jun Han, Qing Peng Sun, Min Lu, Jinbao Pan, Weixiang Wang
Ash1 is a known H3K36-specific histone demethylase that is required for normal Hox gene expression and fertility in Drosophila and mammals. However, little is known about the expression and function of the fungal ortholog of Ash1 in phytopathogenic fungus Magnaporthe oryzae. Here we report that MoKMT2H, an Ash1-like protein, is required for conidium germination and virulence in rice. We obtained MoKMT2H null mutant (ΔMoKMT2H) using a target gene replacement strategy. In the ΔMoKMT2H null mutants, global histone methyltransferase modifications (H3K4me3, H3K9me3, H3K27me3, and H3K36me2/3) of the genome were unaffected...
2016: BioMed Research International
Joo Hwa Lee, Nam Jin Yoo, Min Sung Kim, Sug Hyung Lee
Alterations of genes involved in histone modification are common in cancers. A histone demethylase-encoding gene PHF2 is considered a putative tumor suppressor gene (TSG). PHF2 is essential for p53-mediated TSG functions such as chemotherapy-mediated cancer cell killing. However, inactivating mutations of PHF2 that could inactivate its functions are not reported in cancers. In a genome database, we observed that the PHF2 gene possessed mononucleotide repeats, which could be mutated in cancers with high microsatellite instability (MSI-H)...
October 15, 2016: Pathology Oncology Research: POR
Jianwei Zhang, Qi Li, Shaojin Zhang, Quanquan Xu, Tianen Wang
Lgr4 (leucine-rich repeat domain containing G protein-coupled receptor 4) is implicated in the transcriptional regulation of multiple histone demethylases in the progression of diverse cancers, but there are few reports concerning the molecular mechanism by which Lgr4 regulates histone demethylase activation in prostate cancer (PCa) progression. As Jmjd2a is a histone demethylase, in the current study, we investigated the relationship between interaction Lgr4 with Jmjd 2a and Jmjd2a/androgen receptor (AR) signaling pathway in PCa progression...
October 12, 2016: Experimental Cell Research
Rohit Mathur, Lalit Sehgal, Ondrej Havranek, Stefan Köhrer, Tamer Khashab, Neeraj Jain, Jan A Burger, Sattva S Neelapu, R Eric Davis, Felipe Samaniego
Histone methylation and demethylation regulates B-cell development, and their deregulation correlates with tumor chemoresistance in diffuse large B-cell lymphoma, limiting curative rates. Since histone methylation status correlates with disease aggressiveness and relapse, we investigated the therapeutic potential of inhibiting histone 3 Lys27 demethylase KDM6B, in-vitro, using the small molecule inhibitor GSK-J4. KDM6B is overexpressed in the DLBCL germinal center B-cell subtype, and higher KDM6B levels are associated with worse survival in DLBCL patients treated with R-CHOP...
October 14, 2016: Haematologica
Xiang Yuan, Jinyu Kong, Zhikun Ma, Na Li, Ruinuo Jia, Yiwen Liu, Fuyou Zhou, Qimin Zhan, Gang Liu, Shegan Gao
Our studies investigating the existence of tumor-initiating cell (TIC) populations in human esophageal squamous cell carcinoma (ESCC) had identified a subpopulation of cells isolated from ESCC patient-derived tumor specimens marked by an ALDH(bri+) phenotype bear stem cell-like features. Importantly, KDM4C, a histone demethylase was enhanced in ALDH(bri+) subpopulation, suggesting that strategies interfering with KDM4C may be able to target these putative TICs. In the present study, by genetic and chemical means, we demonstrated that, KDM4C blockade selectively decreased the ESCC ALDH(bri+) TICs population in vitro and specifically targeted the TICs in ALDH(bri+)-derived xenograft, retarding engraftment...
October 2016: Neoplasia: An International Journal for Oncology Research
Nathalie Dehne, Bernhard Brüne
Hypoxia, by activating transcription factors induces transcription of some genes but it also reduces mRNA synthesis by mechanisms that are poorly defined. Activation of human macrophages with interleukin (IL)-4 showed that up-regulation of some IL-4 target genes was reduced when macrophages were incubated at 1% oxygen. Hypoxia impaired induction of chemokine (CC motif) ligand 18 (CCL18), although IL-4-induced DNA binding of the transcription factor STAT6 remained intact. In contrast, induction of serine peptidase inhibitor, Kunitz type (SPINT)2, another IL-4/STAT6 target gene, was not affected by hypoxia...
October 11, 2016: Biochimica et Biophysica Acta
Jianing Zhong, Xianfeng Li, Wanshi Cai, Yan Wang, Shanshan Dong, Jie Yang, Jian'an Zhang, Nana Wu, Yuanyuan Li, Fengbiao Mao, Cheng Zeng, Jinyu Wu, Xingzhi Xu, Zhong Sheng Sun
The Ten Eleven Translocation 1 (TET1) protein is a DNA demethylase that regulates gene expression through altering statue of DNA methylation. However, recent studies have demonstrated that TET1 could modulate transcriptional expression independent of its DNA demethylation activity; yet, the detailed mechanisms underlying TET1's role in such transcriptional regulation remain not well understood. Here, we uncovered that Tet1 formed a chromatin complex with histone acetyltransferase Mof and scaffold protein Sin3a in mouse embryonic stem cells by integrative genomic analysis using publicly available ChIP-seq data sets and a series of in vitro biochemical studies in human cell lines...
October 12, 2016: Nucleic Acids Research
Yoichi Munehira, Ze Yang, Or Gozani
Histone methylation dynamics play a critical role in cellular programming during development. For example, specific lysine methyltransferases (KMTs) and demethylases (KDMs) have been implicated in the differentiation of mesenchymal stem cells into various cell lineages. However, a systematic functional analysis for an entire family of KMT or KDM enzymes has not been performed. Here we test the function of all the known and candidate KDMs in myoblast and osteoblast differentiation using the C2C12 cell differentiation model system...
October 9, 2016: Journal of Molecular Biology
Florian Thaler, Ciro Mercurio
The Jumonji C (JmjC) domain containing histone lysine demethylases have a clear role both in the development and in some diseases including inflammation and cancer. The histone lysine demethylases represent an attractive target for the identification of therapeutic agents and the pyridine derivatives are a scaffolds largely investigated for the identification and development of inhibitors of enzymes of the Jumonji family. This commentary is a scientific evaluation of a patent application US20160102096A1 that describes novel pyridine derivatives in which the introduction of specific substituents is used to modulate the selectivity profile of the inhibitors...
October 12, 2016: Expert Opinion on Therapeutic Patents
Nerea Alonso, Miquel Torrent-Sucarrat, Iosune Arrastia, Ana Arrieta, Fernando P Cossío
The N-demethylation reactions of N,N,N-trimethylpropan-1-ammonium and N,N-dimethyl-, and N-methylpropan-1-aminium cations in the presence of (AcO)2(imidazole)2(H2O)Fe=O complex have been studied by density functional theory. These transformations are suitable models for the N-demethylation of tri-, di-, and monomethylated lysine residues of histones in the presence of Jumonji-C containing histone demethylases. It has been found that the N-demethylation reaction is stepwise and occurs on triplet and quintet potential energy hypersurfaces...
October 11, 2016: Chemistry: a European Journal
Wendy Rosales, Juan Carulla, Jeison García, Diana Vargas, Fernando Lizcano
Epigenetic changes induced by histone demethylases play an important role in differentiation and pathological changes in cardiac cells. However, the role of the jumonji family of demethylases in the development of cardiac hypertrophy remains elusive. In this study, the presence of different histone demethylases in cardiac cells was evaluated after hypertrophy was induced with neurohormones. A cell line from rat cardiomyocytes was used as a biological model. The phenotypic profiles of the cells, as well as the expression of histone demethylases, were studied through immunofluorescence, transient transfection, western blot, and qRT-PCR analysis after inducing hypertrophy by angiotensin II and endothelin-1...
2016: BioMed Research International
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 6, 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
N K Singhal, H Huang, S Li, R Clements, J Gadd, A Daniels, E E Kooijman, P Bannerman, T Burns, F Guo, D Pleasure, E Freeman, L Shriver, J McDonough
The neuronal mitochondrial metabolite N-acetylaspartate (NAA) is decreased in the multiple sclerosis (MS) brain. NAA is synthesized in neurons by the enzyme N-acetyltransferase-8-like (NAT8L) and broken down in oligodendrocytes by aspartoacylase (ASPA) into acetate and aspartate. We have hypothesized that NAA links the metabolism of axons with oligodendrocytes to support myelination. To test this hypothesis, we performed lipidomic analyses using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance thin-layer chromatography (HPTLC) to identify changes in myelin lipid composition in postmortem MS brains and in NAT8L knockout (NAT8L(-/-)) mice which do not synthesize NAA...
October 5, 2016: Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale
A Silvina Nacht, Miguel Beato, Guillermo P Vicent
How genes are repressed by steroid hormones remains a matter of debate and several indirect mechanisms have been proposed. We found that the ligand-activated progesterone receptor (PR) recruits to the promoter of down-regulated genes a repressor complex composed of HP1γ, the lysine demethylase LSD1, histone deacetylases, coREST, the RNA SRA and the ATPase BRG1. BRG1 is needed for chromatin remodeling and facilitates the deposition of linker histone variant H1.2, which compacts chromatin and hinders RNA polymerase loading and transcription...
October 4, 2016: Transcription
Yuhua Wang, Xueyi Xue, Jian-Kang Zhu, Juan Dong
DNA methylation and histone modifications interplay to modulate gene expression in biological organisms. The histone demethylase IBM1 suppresses DNA methylation and gene silencing, primarily by targeting genic regions in the Arabidopsis genome. The chromatin regulator EMD2 is also required for prevention of genic DNA methylation because it maintains IBM1 expression by promoting IBM1 mRNA distal polyadenylation. Loss-of-function ibm1 and edm2 mutant plants display a wide range of developmental defects, but little is known about what developmentally important genes are regulated by IBM1 and EDM2...
October 3, 2016: Development
Zhiying Huang, Qiuju Huang, Liyan Ji, Ying Wang, Xiaoxiao Qi, Liang Liu, Zhongqiu Liu, Linlin Lu
Epigenetic modifications include DNA methylation, histone modification, and other patterns. These processes are associated with carcinogenesis and cancer progression. Thus, epigenetic modification-related enzymes, such as DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), histone demethylases (HDMTs), histone acetyltransferases (HATs), and histone deacetylases (HDACs), as well as some related proteins, including methyl-CpG binding proteins (MBPs) and DNMT1-associated protein (DMAP 1), are considered as potential targets for cancer prevention and therapy...
September 30, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Yunhui Peng, Emil Alexov
The KDM5C gene (also known as JARID1C and SMCX) is located on the X chromosome and encodes a ubiquitously expressed 1560-aa protein, which plays an important role in lysine methylation (specifically reverses tri- and di-methylation of Lys4 of histone H3). Currently, 13 missense mutations in KDM5C have been linked to X-linked mental retardation. However, the molecular mechanism of disease is currently unknown due to the experimental difficulties in expressing such large protein and the lack of experimental 3D structure...
October 1, 2016: Proteins
Zahra Eelaminejad, Raha Favaedi, Niloofar Sodeifi, Mohammad Ali Sadighi Gilani, Maryam Shahhoseini
JMJD1A (jumonji domain-containing 1A), a known histone H3K9 demethylase, has been identified as a critical epigenetic regulator in male germ cells, activating the sperm chromatin-packaging genes encoding protamines (PRM) and transition proteins (TNP) required for spermatid elongation and condensation. This research investigated the expression pattern of JMJD1A protein in testicular biopsies of 79 infertile men who had undergone testicular sperm extraction. Samples were classified into obstructive azoospermia (OA, n = 26), round spermatid maturation arrest (SMA, n = 29) and Sertoli cell only syndrome (SCOS, n = 24)...
September 22, 2016: Reproductive Biomedicine Online
Peterson Kariuki Maina, Peng Shao, Qi Liu, Ladan Fazli, Scott Tyler, Moman Nasir, Xuesen Dong, Hank Heng Qi
Epigenetic factors play critical roles in prostate cancer (PCa) development. However, how they contribute to neuroendocrine differentiation (NED) and castration-resistant PCa (CRPC) is not fully understood. Using bioinformatics and biochemical approaches to analyze cell-based models of NED and CRPC, we found a cluster of epigenetic factors whose expression is downregulated during NED and upregulated in CRPC (i.e. follow a Down-Up pattern). Two histone demethylases within this cluster, PHF8 and KDM3A, are post-transcriptionally regulated by c-MYC through miR-22, which targets both PHF8 and KDM3A...
September 28, 2016: Oncotarget
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