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Lysine specific demethylase

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
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
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
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
S Ramadoss, S Sen, I Ramachandran, S Roy, G Chaudhuri, R Farias-Eisner
Ovarian cancer is the leading cause of death among all gynecological malignancies due to the development of acquired chemoresistance and disease relapse. Although the role of cancer stem cells (CSCs), a subset of tumor cells with the self-renewal and differentiation capabilities, in therapeutic resistance is beginning to be better understood, the significance of epigenetic regulatory mechanisms responsible for integrating the stemness with drug resistance remain poorly understood. Here we identified that lysine demethylase KDM3A as a critical regulator of ovarian cancer stemness and cisplatin resistance by inducing the expressions of pluripotent molecules Sox2 and Nanog and anti-apoptotic B-cell lymphoma 2 (Bcl-2), respectively...
October 3, 2016: Oncogene
Yifan Lian, Juan Wang, Jing Feng, Jie Ding, Zhonghua Ma, Juan Li, Peng Peng, Wei De, Keming Wang
Long non-coding RNA (lncRNA) modulates gene expression, while lncRNA dysregulation is associated with human cancer. Furthermore, while recent studies have shown that lncRNA IRAIN plays an important role in other malignancies, the role of IRAIN in pancreatic cancer (PC) progression remains unclear. In this study, we found that upregulation of lncRNA IRAIN was significantly correlated with tumor size, TNM stage, and lymph node metastasis in a cohort of 37 PC patients. In vitro experiments showed that knockdown of IRAIN by small interfering RNA (siRNA) significantly induced cell apoptosis and inhibited cell proliferation in both BxPC-3 and PANC-1 cells...
September 19, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Yan Chen, Jeesun Kim, Ruipeng Zhang, Xiaoqin Yang, Yong Zhang, Jianwu Fang, Zhui Chen, Lin Teng, Xiaowei Chen, Hui Ge, Peter Atadja, En Li, Taiping Chen, Wei Qi
Adipose tissue plays important roles in animals. White fat stores energy in lipids, while brown fat is responsible for nonshivering thermogenesis through UCP1-mediated energy dissipation. Although epigenetic mechanisms modulate differentiation in multiple lineages, the epigenetic regulation of brown adipocyte differentiation is poorly understood. By screening a collection of epigenetic compounds, we found that Lysine-Specific Demethylase 1 (LSD1) inhibitors repress brown adipocyte differentiation. RNAi-mediated Lsd1 knockdown causes a similar effect, which can be rescued by expression of wild-type but not catalytic-inactive LSD1...
September 9, 2016: Cell Chemical Biology
Christie C Sze, Ali Shilatifard
During development, precise spatiotemporal patterns of gene expression are coordinately controlled by cis-regulatory modules known as enhancers. Their crucial role in development helped spur numerous studies aiming to elucidate the functional properties of enhancers within their physiological and disease contexts. In recent years, the role of enhancer malfunction in tissue-specific tumorigenesis is increasingly investigated. Here, we direct our focus to two primary players in enhancer regulation and their role in cancer pathogenesis: MLL3 and MLL4, members of the COMPASS family of histone H3 lysine 4 (H3K4) methyltransferases, and their complex-specific subunit UTX, a histone H3 lysine 27 (H3K27) demethylase...
September 16, 2016: Cold Spring Harbor Perspectives in Medicine
Lei Yi, Yan Cui, Qingfu Xu, Yugang Jiang
The substrates and mechanisms of ubiquitin specific peptidase 7 (USP7) in glioma remain unclear. Lysine‑specific demethylase 1 (LSD1) may undergo proteasomal degradation; however, a reciprocal mechanism that stabilizes LSD1 in glioma has not been dertermined. Here co-immunoprecipitation and GST pull-down assays revealed that LSD1 is associated with USP7 in vivo and in vitro. USP7 inhibited LSD1 ubiquitination and stabilized LSD1 in A172 and T98G cells. MTT, EdU proliferation, flow cytometry and Transwell assays indicated that LSD1 played a critical role in the proliferation and invasion of glioblastoma (GBM) cells...
September 16, 2016: Oncology Reports
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...
September 2016: Anticancer Research
Valentina Speranzini, Dante Rotili, Giuseppe Ciossani, Simona Pilotto, Biagina Marrocco, Mariantonietta Forgione, Alessia Lucidi, Federico Forneris, Parinaz Mehdipour, Sameer Velankar, Antonello Mai, Andrea Mattevi
Because of its involvement in the progression of several malignant tumors, the histone lysine-specific demethylase 1 (LSD1) has become a prominent drug target in modern medicinal chemistry research. We report on the discovery of two classes of noncovalent inhibitors displaying unique structural features. The antibiotics polymyxins bind at the entrance of the substrate cleft, where their highly charged cyclic moiety interacts with a cluster of positively charged amino acids. The same site is occupied by quinazoline-based compounds, which were found to inhibit the enzyme through a most peculiar mode because they form a pile of five to seven molecules that obstruct access to the active center...
September 2016: Science Advances
Jun Xiao, Un-Sa Lee, Doris Wagner
Histone lysine methylation plays a fundamental role in the epigenetic regulation of gene expression in multicellular eukaryotes, including plants. It shapes plant developmental and growth programs as well as responses to the environment. The methylation status of certain amino-acids, in particular of the histone 3 (H3) lysine tails, is dynamically controlled by opposite acting histone methyltransferase 'writers' and histone demethylase 'erasers'. The methylation status is interpreted by a third set of proteins, the histone modification 'readers', which specifically bind to a methylated amino-acid on the H3 tail...
September 7, 2016: Current Opinion in Plant Biology
Ana Fiszbein, Alberto R Kornblihtt
Alternative splicing, as well as chromatin structure, greatly contributes to specific transcriptional programs that promote neuronal differentiation. The activity of G9a, the enzyme responsible for mono- and di-methylation of lysine 9 on histone H3 (H3K9me1 and H3K9me2) in mammalian euchromatin, has been widely implicated in the differentiation of a variety of cell types and tissues. In a recent work from our group (Fiszbein et al., 2016) we have shown that alternative splicing of G9a regulates its nuclear localization and, therefore, the efficiency of H3K9 methylation, which promotes neuronal differentiation...
2016: Neurogenesis (Austin, Tex.)
Jean Z Lin, Stephen R Farmer
In this issue of Genes & Development, Zeng and colleagues (pp. 1822-1836) identify lysine-specific demethylase 1 (LSD1) as a pivotal regulator of whole-body energy expenditure by controlling the oxidative and thermogenic activity of brown adipose tissue (BAT). They show that LSD1 interacts with PRDM16 to repress select white adipose tissue (WAT) genes but also represses hydroxysteroid 11-β-dehydrogenase 1 (HSD11B1) independently of PRDM16 to prevent production of glucocorticoids that impair BAT functions. Their study provides important insight into epigenetic mechanisms regulating the function of BAT...
August 15, 2016: Genes & Development
Yingchun Cui, Nian Liu, Fuzhe Ma, Weixia Sun, Hao Wu, Zhonggao Xu, Hang Yuan
The aim of the present study was to examine the impacts and mechanisms of 12‑lipoxygenase (12‑LO) and its metabolites on the acetylation and methylation of histone‑3‑lysine (H3K) in the p21 gene. Rat mesangial cells (MCs) were selected for use in the present study. A chromatin immunoprecipitation assay, reverse transcription‑quantitative polymerase chain reaction analysis and a luciferase assay were used to detect transcriptional activities, the acetylation (Ac) of H3K (H3KAc), p21 promoter methylation (Me) and the transcription regions induced by 12 (S)‑hydroxyeicosatetraenoic acid (HETE)...
October 2016: Molecular Medicine Reports
Yvonne C Lussi, Luca Mariani, Carsten Friis, Juhani Peltonen, Toshia R Myers, Claudia Krag, Garry Wong, Anna Elisabetta Salcini
Methylation of Histone 3 Lysine 4 (H3K4) is largely associated with promoters and enhancers of actively transcribed genes and it is finely regulated during development by the action of histone methyltransferases and demethylases. H3K4me3 demethylases of the KDM5 family have been previously implicated in development, but how the regulation of H3K4me3 level controls developmental processes is not fully established. Here, we show that the H3K4 demethylase RBR-2, the unique member of the KDM5 family in C. elegans, acts cell-autonomously and in a catalytic-dependent manner to control vulva precursor cells fate acquisition, by promoting the LIN-12/Notch pathway...
August 30, 2016: Development
Bing-Xian Chen, Wen-Yan Li, Yin-Tao Gao, Zhong-Jian Chen, Wei-Na Zhang, Qin-Jian Liu, Zhuang Chen, Jun Liu
Seed germination is a complicated biological process that requires regulated enzymatic and non-enzymatic reactions. The action of polyamine oxidase (PAO) produces hydrogen peroxide (H2O2), which promotes dicot seed germination. However, whether and, if so, how PAOs regulate monocot seed germination via H2O2 production is unclear. Herein, we report that the coleorhiza is the main physical barrier to radicle protrusion during germination of rice seed (a monocot seed) and that it does so in a manner similar to that of dicot seed micropylar endosperm...
2016: Frontiers in Plant Science
Xing Zeng, Mark P Jedrychowski, Yi Chen, Sara Serag, Gareth G Lavery, Steve P Gygi, Bruce M Spiegelman
Brown adipocytes display phenotypic plasticity, as they can switch between the active states of fatty acid oxidation and energy dissipation versus a more dormant state. Cold exposure or β-adrenergic stimulation favors the active thermogenic state, whereas sympathetic denervation or glucocorticoid administration promotes more lipid accumulation. Our understanding of the molecular mechanisms underlying these switches is incomplete. Here we found that LSD1 (lysine-specific demethylase 1), a histone demethylase, regulates brown adipocyte metabolism in two ways...
August 15, 2016: Genes & Development
Nhan T Ho, Julia V Busik, James H Resau, Nigel Paneth, Sok Kean Khoo
Unfrozen archived newborn blood spots (NBS) have been shown to retain sufficient messenger RNA (mRNA) for gene expression profiling. However, the effect of storage time at ambient temperature for NBS samples in relation to the quality of gene expression data is relatively unknown. Here, we evaluated mRNA expression from quantitative real-time PCR (qRT-PCR) and microarray data obtained from NBS samples stored at ambient temperature to determine the effect of storage time on the quality of gene expression. These data were generated in a previous case-control study examining NBS in 53 children with cerebral palsy (CP) and 53 matched controls...
August 18, 2016: Molecular Genetics and Metabolism
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