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Histone demethylases

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https://www.readbyqxmd.com/read/29772566/the-epigenetic-factor-kdm2b-regulates-emt-and-small-gtpases-in-colon-tumor-cells
#1
Nefeli Zacharopoulou, Anna Tsapara, Galatea Kallergi, Evi Schmid, Saad Alkahtani, Saud Alarifi, Philip N Tsichlis, Sotirios C Kampranis, Christos Stournaras
BACKGROUND/AIMS: The epigenetic factor KDM2B is a histone demethylase expressed in various tumors. Recently, we have shown that KDM2B regulates actin cytoskeleton organization, small Rho GTPases signaling, cell-cell adhesion and migration of prostate tumor cells. In the present study, we addressed its role in regulating EMT and small GTPases expression in colon tumor cells. METHODS: We used RT-PCR for the transcriptional analysis of various genes, Western blotting for the assessment of protein expression and immunofluorescence microscopy for visualization of fluorescently labeled proteins...
May 14, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29769286/targeted-inhibition-of-histone-h3k27-demethylation-is-effective-in-high-risk-neuroblastoma
#2
Timothy L Lochmann, Krista M Powell, Jungoh Ham, Konstantinos V Floros, Daniel A R Heisey, Richard I J Kurupi, Marissa L Calbert, Maninderjit S Ghotra, Patricia Greninger, Mikhail Dozmorov, Madhu Gowda, Andrew J Souers, C Patrick Reynolds, Cyril H Benes, Anthony C Faber
High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death...
May 16, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29768411/cytoskeleton-structure-and-total-methylation-of-mouse-cardiac-and-lung-tissue-during-space-flight
#3
Irina V Ogneva, Sergey S Loktev, Vladimir N Sychev
The purpose of this work was to evaluate the protein and mRNA expression levels of multiple cytoskeletal proteins in the cardiac and lung tissue of mice that were euthanized onboard the United States Orbital Segment of the International Space Station 37 days after the start of the SpaceX-4 mission (September 2014, USA). The results showed no changes in the cytoskeletal protein content in the cardiac and lung tissue of the mice, but there were significant changes in the mRNA expression levels of the associated genes, which may be due to an increase in total genome methylation...
2018: PloS One
https://www.readbyqxmd.com/read/29766333/treatment-of-donor-cells-with-recombinant-kdm4d-protein-improves-preimplantation-development-of-cloned-ovine-embryos
#4
Yumei Zhang, Qianqian Wang, Kailing Liu, Enen Gao, Hong Guan, Jian Hou
Incomplete epigenetic reprogramming is one of the major factors affecting the development of embryos cloned by somatic cell nuclear transfer (SCNT). Histone 3 lysine 9 (H3K9) trimethylation has been identified as a key barrier to efficient reprogramming by SCNT. The aim of this study was to explore a method of downregulating H3K9me3 levels in donor cells by using histone lysine demethylase (KDM) protein. When sheep fetal fibroblast cells were treated with recombinant human KDM4D protein (rhKDM4D), the levels of H3K9 trimethylation and dimethylation were both significantly decreased...
May 15, 2018: Cytotechnology
https://www.readbyqxmd.com/read/29765516/selective-dissociation-between-lsd1-and-gfi1b-by-a-lsd1-inhibitor-ncd38-induces-the-activation-of-erg-super-enhancer-in-erythroleukemia-cells
#5
Ryusuke Yamamoto, Masahiro Kawahara, Shinji Ito, Junko Satoh, Goichi Tatsumi, Masakatsu Hishizawa, Takayoshi Suzuki, Akira Andoh
Lysine-specific demethylase 1 (LSD1) is a histone modifier for transcriptional repression involved in the regulation of hematopoiesis. We previously reported that a LSD1 inhibitor NCD38 induces transdifferentiation from erythroid lineage to granulomonocytic lineage and exerts anti-leukemia effect through de-repression of the specific super-enhancers of hematopoietic regulators including ERG in a human erythroleukemia cell line, HEL. However, the mechanistic basis for this specificity of NCD38 has remained unclear...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29764901/the-histone-demethylase-kdm5-is-essential-for-larval-growth-in-drosophila
#6
Coralie Drelon, Helen M Belalcazar, Julie Secombe
Regulated gene expression is necessary for developmental and homeostatic processes. The KDM5 family of transcriptional regulators are histone H3 lysine 4 demethylases that can function through both demethylase-dependent and independent mechanisms. While loss and overexpression of KDM5 proteins are linked to intellectual disability and cancer, respectively, their normal developmental functions remain less characterized. Drosophila melanogaster provides an ideal system to investigate KDM5 function, as it encodes a single ortholog in contrast to the four paralogs found in mammalian cells...
May 15, 2018: Genetics
https://www.readbyqxmd.com/read/29764755/investigations-on-small-molecule-inhibitors-targeting-the-histone-h3k4-tri-methyllysine-binding-phd-finger-of-jmjc-histone-demethylases
#7
REVIEW
Bhaskar Bhushan, Alexandre Erdmann, Yijia Zhang, Roman Belle, Catrine Johannson, Udo Oppermann, Richard J Hopkinson, Christopher J Schofield, Akane Kawamura
Plant homeodomain (PHD) containing proteins are important epigenetic regulators and are of interest as potential drug targets. Inspired by the amiodarone derivatives reported to inhibit the PHD finger 3 of KDM5A (KDM5A(PHD3)), a set of compounds were synthesised. Amiodarone and its derivatives were observed to weakly disrupt the interactions of a histone H3K4me3 peptide with KDM5A(PHD3). Selected amiodarone derivatives inhibited catalysis of KDM5A, but in a PHD-finger independent manner. Amiodarone derivatives also bind to H3K4me3-binding PHD-fingers from the KDM7 subfamily...
March 19, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29763382/kdm2b-is-a-histone-h3k79-demethylase-and-induces-transcriptional-repression-via-sirtuin-1-mediated-chromatin-silencing
#8
Joo-Young Kang, Ji-Young Kim, Kee-Beom Kim, Jin Woo Park, Hana Cho, Ja Young Hahm, Yun-Cheol Chae, Daehwan Kim, Hyun Kook, Sangmyeong Rhee, Nam-Chul Ha, Sang-Beom Seo
The methylation of histone H3 lysine 79 (H3K79) is an active chromatin marker and is prominent in actively transcribed regions of the genome; however, demethylase of H3K79 remains unknown despite intensive research. Here, we show that KDM2B, also known as FBXL10 and a member of the Jumonji C family of proteins known for its histone H3K36 demethylase activity, is a di- and trimethyl H3K79 demethylase. We demonstrate that KDM2B induces transcriptional repression of HOXA7 and MEIS1 via occupancy of promoters and demethylation of H3K79...
May 15, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29757189/notch-effector-csl-promotes-squamous-cell-carcinoma-by-repressing-histone-demethylase-kdm6b
#9
Dania Al Labban, Seung-Hee Jo, Paola Ostano, Chiara Saglietti, Massimo Bongiovanni, Renato Panizzon, G Paolo Dotto
Notch 1/2 genes play tumor-suppressing functions in squamous cell carcinoma (SCC), a very common malignancy in skin and internal organs. In contrast with Notch, we show that the transcription factor CSL (also known as RBP-Jκ), a key effector of canonical Notch signaling endowed with intrinsic transcription-repressive functions, plays a tumor-promoting function in SCC development. Expression of this gene decreased in upper epidermal layers and human keratinocytes (HKCs) undergoing differentiation, while it increased in premalignant and malignant SCC lesions from skin, head/neck, and lung...
May 14, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29753027/jmjd3-inhibition-protects-against-isoproterenol-induced-cardiac-hypertrophy-by-suppressing-%C3%AE-mhc-expression
#10
Zhen Guo, Jing Lu, Jingyan Li, Panxia Wang, Zhenzhen Li, Yao Zhong, Kaiteng Guo, Junjian Wang, Jiantao Ye, Peiqing Liu
Jumonji domain-containing protein D3 (JMJD3), a histone 3 lysine 27 (H3K27) demethylase, has been extensively studied for their participation in development, cellular physiology and a variety of diseases. However, its potential roles in cardiovascular system remain unknown. In this study, we found that JMJD3 played a pivotal role in the process of cardiac hypertrophy. JMJD3 expression was elevated by isoproterenol (ISO) stimuli both in vitro and in vivo. Overexpression of wild-type JMJD3, but not the demethylase-defective mutant, promoted cardiomyocyte hypertrophy, as implied by increased cardiomyocyte surface area and the expression of hypertrophy marker genes...
May 9, 2018: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/29748283/the-histone-demethylase-kdm6b-regulates-temperature-dependent-sex-determination-in-a-turtle-species
#11
Chutian Ge, Jian Ye, Ceri Weber, Wei Sun, Haiyan Zhang, Yingjie Zhou, Cheng Cai, Guoying Qian, Blanche Capel
Temperature-dependent sex determination is a notable model of phenotypic plasticity. In many reptiles, including the red-eared slider turtle Trachemys scripta elegans ( T. scripta ), the individual's sex is determined by the ambient temperature during egg incubation. In this study, we show that the histone H3 lysine 27 (H3K27) demethylase KDM6B exhibits temperature-dependent sexually dimorphic expression in early T. scripta embryos before the gonad is distinct. Knockdown of Kdm6b at 26°C (a temperature at which all offspring develop into males) triggers male-to-female sex reversal in >80% of surviving embryos...
May 11, 2018: Science
https://www.readbyqxmd.com/read/29748167/kdm5b-decommissions-the-h3k4-methylation-landscape-of-self-renewal-genes-during-trophoblast-stem-cell-differentiation
#12
Jian Xu, Benjamin L Kidder
Trophoblast stem (TS) cells derived from the trophectoderm (TE) of mammalian embryos have the ability to self-renew indefinitely or differentiate into fetal lineages of the placenta. Epigenetic control of gene expression plays an instrumental role in dictating the fate of TS cell self-renewal and differentiation. However, the roles of histone demethylases and activating histone modifications such as methylation of histone 3 lysine 4 (H3K4me3/me2) in regulating TS cell expression programs, and in priming the epigenetic landscape for trophoblast differentiation, are largely unknown...
May 10, 2018: Biology Open
https://www.readbyqxmd.com/read/29741645/lsd1-coordinates-with-the-sin3a-hdac-complex-and-maintains-sensitivity-to-chemotherapy-in-breast-cancer
#13
Yang Yang, Wei Huang, Rongfang Qiu, Ruiqiong Liu, Yi Zeng, Jie Gao, Yu Zheng, Yongqiang Hou, Shuang Wang, Wenqian Yu, Shuai Leng, Dandan Feng, Yan Wang
Lysine-specific demethylase 1 (LSD1) was the first histone demethylase identified as catalysing the removal of mono- and di-methylation marks on histone H3-K4. Despite the potential broad action of LSD1 in transcription regulation, recent studies indicate that LSD1 may coordinate with multiple epigenetic regulatory complexes including CoREST/HDAC complex, NuRD complex, SIRT1, and PRC2, implying complicated mechanistic actions of this seemingly simple enzyme. Here, we report that LSD1 is also an integral component of the SIN3A/HDAC complex...
May 7, 2018: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29736013/utx-mediated-enhancer-and-chromatin-remodeling-suppresses-myeloid-leukemogenesis-through-noncatalytic-inverse-regulation-of-ets-and-gata-programs
#14
Malgorzata Gozdecka, Eshwar Meduri, Milena Mazan, Konstantinos Tzelepis, Monika Dudek, Andrew J Knights, Mercedes Pardo, Lu Yu, Jyoti S Choudhary, Emmanouil Metzakopian, Vivek Iyer, Haiyang Yun, Naomi Park, Ignacio Varela, Ruben Bautista, Grace Collord, Oliver Dovey, Dimitrios A Garyfallos, Etienne De Braekeleer, Saki Kondo, Jonathan Cooper, Berthold Göttgens, Lars Bullinger, Paul A Northcott, David Adams, George S Vassiliou, Brian J P Huntly
The histone H3 Lys27-specific demethylase UTX (or KDM6A) is targeted by loss-of-function mutations in multiple cancers. Here, we demonstrate that UTX suppresses myeloid leukemogenesis through noncatalytic functions, a property shared with its catalytically inactive Y-chromosome paralog, UTY (or KDM6C). In keeping with this, we demonstrate concomitant loss/mutation of KDM6A (UTX) and UTY in multiple human cancers. Mechanistically, global genomic profiling showed only minor changes in H3K27me3 but significant and bidirectional alterations in H3K27ac and chromatin accessibility; a predominant loss of H3K4me1 modifications; alterations in ETS and GATA-factor binding; and altered gene expression after Utx loss...
May 7, 2018: Nature Genetics
https://www.readbyqxmd.com/read/29734782/design-synthesis-and-in-vitro-evaluation-of-novel-histone-h3-peptide-based-lsd1-inactivators-incorporating-%C3%AE-%C3%AE-disubstituted-amino-acids-with-%C3%AE-turn-inducing-structures
#15
Yosuke Ota, Taeko Kakizawa, Yukihiro Itoh, Takayoshi Suzuki
Lysine-specific demethylase 1 (LSD1) mainly removes methyl groups of mono- or di-methylated lysine residues at the fourth position of histone H3 to epigenetically regulate the expression of genes associated with several diseases, such as cancer. Therefore, LSD1 inactivators are expected to be used as therapeutic agents. In this study, to identify novel peptide-based LSD1 inactivators, we focused on the X-ray structure of LSD1 complexed with a H3 peptide-based suicide substrate. It has been proposed that a methylated histone substrate forms three consecutive γ-turn structures in the active pocket of LSD1...
May 6, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29725259/expanding-the-oro-dental-and-mutational-spectra-of-kabuki-syndrome-and-expression-of-kmt2d-and-kdm6a-in-human-tooth-germs
#16
Thantrira Porntaveetus, Mushriq F Abid, Thanakorn Theerapanon, Chalurmpon Srichomthong, Atsushi Ohazama, Katsushige Kawasaki, Maiko Kawasaki, Kanya Suphapeetiporn, Paul T Sharpe, Vorasuk Shotelersuk
Kabuki syndrome is a rare genetic disorder characterized by distinct dysmorphic facial features, intellectual disability, and multiple developmental abnormalities. Despite more than 350 documented cases, the oro-dental spectrum associated with kabuki syndrome and expression of KMT2D (histone-lysine N-methyltransferase 2D) or KDM6A (lysine-specific demethylase 6A) genes in tooth development have not been well defined. Here, we report seven unrelated Thai patients with Kabuki syndrome having congenital absence of teeth, malocclusion, high-arched palate, micrognathia, and deviated tooth shape and size...
2018: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/29724526/vitamin-c-in-stem-cell-reprogramming-and-cancer
#17
REVIEW
Luisa Cimmino, Benjamin G Neel, Iannis Aifantis
Vitamin C is an essential dietary requirement for humans. In addition to its known role as an antioxidant, vitamin C is a cofactor for Fe2+ - and α-ketoglutarate-dependent dioxygenases (Fe2+ /α-KGDDs) which comprise a large number of diverse enzymes, including collagen prolyl hydroxylases and epigenetic regulators of histone and DNA methylation. Vitamin C can modulate embryonic stem cell (ESC) function, enhance reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs), and hinder the aberrant self-renewal of hematopoietic stem cells (HSCs) through its ability to enhance the activity of either Jumonji C (JmjC) domain-containing histone demethylases or ten-eleven translocation (TET) DNA hydroxylases...
April 30, 2018: Trends in Cell Biology
https://www.readbyqxmd.com/read/29720215/dependence-receptor-unc5a-restricts-luminal-to-basal-breast-cancer-plasticity-and-metastasis
#18
Maria B Padua, Poornima Bhat-Nakshatri, Manjushree Anjanappa, Mayuri S Prasad, Yangyang Hao, Xi Rao, Sheng Liu, Jun Wan, Yunlong Liu, Kyle McElyea, Max Jacobsen, George Sandusky, Sandra Althouse, Susan Perkins, Harikrishna Nakshatri
BACKGROUND: The majority of estrogen receptor-positive (ERα+ ) breast cancers respond to endocrine therapies. However, resistance to endocrine therapies is common in 30% of cases, which may be due to altered ERα signaling and/or enhanced plasticity of cancer cells leading to breast cancer subtype conversion. The mechanisms leading to enhanced plasticity of ERα-positive cancer cells are unknown. METHODS: We used short hairpin (sh)RNA and/or the CRISPR/Cas9 system to knockdown the expression of the dependence receptor UNC5A in ERα+ MCF7 and T-47D cell lines...
May 2, 2018: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29718303/the-kdm4a-kdm4c-nf-%C3%AE%C2%BAb-and-wdr5-epigenetic-cascade-regulates-the-activation-of-b-cells
#19
Kuo-Hsuan Hung, Yong H Woo, I-Ying Lin, Chin-Hsiu Liu, Li-Chieh Wang, Hsin-Yu Chen, Bor-Luen Chiang, Kuo-I Lin
T follicular helper (Tfh) cell-derived signals promote activation and proliferation of antigen-primed B cells. It remains unclear whether epigenetic regulation is involved in the B cell responses to Tfh cell-derived signals. Here, we demonstrate that Tfh cell-mimicking signals induce the expression of histone demethylases KDM4A and KDM4C, and the concomitant global down-regulation of their substrates, H3K9me3/me2, in B cells. Depletion of KDM4A and KDM4C potentiates B cell activation and proliferation in response to Tfh cell-derived signals...
April 30, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29712835/histone-demethylase-jmjd1a-promotes-alternative-splicing-of-ar-variant-7-ar-v7-in-prostate-cancer-cells
#20
Lingling Fan, Fengbo Zhang, Songhui Xu, Xiaolu Cui, Arif Hussain, Ladan Fazli, Martin Gleave, Xuesen Dong, Jianfei Qi
Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo...
April 30, 2018: Proceedings of the National Academy of Sciences of the United States of America
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