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https://www.readbyqxmd.com/read/29339538/e6-protein-expressed-by-high-risk-hpv-activates-super-enhancers-of-the-egfr-and-c-met-oncogenes-by-destabilizing-the-histone-demethylase-kdm5c
#1
Xiaohua Chen, Jun Xian Loo, Xin Shi, Wenjun Xiong, Yong Guo, Haiqiang Ke, Mingkun Yang, Yanping Jiang, Siyu Xia, Min Zhao, Shan Zhong, ChunJiang He, Li Fu, Feng Li
The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events are poorly understood. Here we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner...
January 16, 2018: Cancer Research
https://www.readbyqxmd.com/read/29324315/histone-demethylase-kdm5a-inhibits-glioma-cells-migration-and-invasion-by-down-regulating-zeb1
#2
Bin Dai, Hui Huang, Feng Guan, Guangtong Zhu, Zhiyong Xiao, Beibei Mao, Haiyang Su, Zhiqiang Hu
Malignant gliomas are highly lethal cancers worldwide as tumor cells infiltrate to healthy brain tissue invariably. Histone demethylase KDM5A as an oncogene or tumor suppressor in cancer still has been controversial. KDM5A may have a different function in different type cancer cells. However, the specific roles of KDM5A in the progression of glioma remain undiscovered. In this study, we found that compared with primary glioma, metastasis glioma had low KDM5A levels. Besides, lower KDM5A levels were linked to poor survival in glioma cancer patients, indicating that KDM5A is a new prognostic marker for glioma cancer...
January 8, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29323282/mll2-conveys-transcription-independent-h3k4-trimethylation-in-oocytes
#3
Courtney W Hanna, Aaron Taudt, Jiahao Huang, Lenka Gahurova, Andrea Kranz, Simon Andrews, Wendy Dean, A Francis Stewart, Maria Colomé-Tatché, Gavin Kelsey
Histone 3 K4 trimethylation (depositing H3K4me3 marks) is typically associated with active promoters yet paradoxically occurs at untranscribed domains. Research to delineate the mechanisms of targeting H3K4 methyltransferases is ongoing. The oocyte provides an attractive system to investigate these mechanisms, because extensive H3K4me3 acquisition occurs in nondividing cells. We developed low-input chromatin immunoprecipitation to interrogate H3K4me3, H3K27ac and H3K27me3 marks throughout oogenesis. In nongrowing oocytes, H3K4me3 was restricted to active promoters, but as oogenesis progressed, H3K4me3 accumulated in a transcription-independent manner and was targeted to intergenic regions, putative enhancers and silent H3K27me3-marked promoters...
January 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29322246/de-novo-variants-in-setd1b-are-associated-with-intellectual-disability-epilepsy-and-autism
#4
Takuya Hiraide, Mitsuko Nakashima, Kaori Yamoto, Tokiko Fukuda, Mitsuhiro Kato, Hiroko Ikeda, Yoko Sugie, Kazushi Aoto, Tadashi Kaname, Kazuhiko Nakabayashi, Tsutomu Ogata, Naomichi Matsumoto, Hirotomo Saitsu
SETD1B (SET domain containing 1B) is a component of SET1 histone methyltransferase complex, which mediates the methylation of histone H3 on lysine 4 (H3K4). Here, we describe two unrelated individuals with de novo variants in SETD1B identified by trio-based whole exome sequencing: c.5524C>T, p.(Arg1842Trp) and c.5575C>T, p.(Arg1859Cy). The two missense variants occurred at evolutionarily conserved amino acids and are located within the SET domain, which plays a pivotal role in catalyzing histone methylation...
January 10, 2018: Human Genetics
https://www.readbyqxmd.com/read/29312470/combined-inhibition-of-bet-proteins-and-class-i-hdacs-synergistically-induces-apoptosis-in-urothelial-carcinoma-cell-lines
#5
Alexander S Hölscher, Wolfgang A Schulz, Maria Pinkerneil, Günter Niegisch, Michèle J Hoffmann
Background: New efficient therapies for urothelial carcinoma (UC) are urgently required. Small-molecule drugs targeting chromatin regulators are reasonable candidates because these regulators are frequently mutated or deregulated in UC. Indeed, in previous work, Romidepsin, which targets class I histone deacetylases (HDAC), efficiently killed UC cells, but did not elicit canonical apoptosis and affected benign urothelial cells indiscriminately. Combinations of HDAC inhibitors with JQ1, an inhibitor of bromodomain-containing acetylation reader proteins like BRD4, which promote especially the transcription of pro-tumorigenic genes, have shown efficacy in several tumor types...
2018: Clinical Epigenetics
https://www.readbyqxmd.com/read/29288791/chromatin-modifications-of-htert-gene-in-htert-immortalized-human-mesenchymal-stem-cells-upon-exposure-to-radiation
#6
Nedime Serakinci, Pınar Mega Tiber, Oya Orun
Regulation of telomerase activity is thought to participate in the cellular response to ionizing radiation. Epigenetic mechanisms play a role in this regulation, as well as other mechanisms such as transcription, phosphorylation, etc. Here, we investigated chromatin modifications in telomerase promoter upon exposure to ionizing radiation in human mesenchymal stem cells (hMSC) and telomerase-immortalized hMSCs (hMSC-telo1) together with a hMSC-telo1 cell line in which TRF2 expression was partially repressed (siTRF2 hMSC-telo1)...
December 27, 2017: European Journal of Medical Genetics
https://www.readbyqxmd.com/read/29288530/pka-binding-domain-of-akap8-is-essential-for-direct-interaction-with-dpy30-protein
#7
Anna Bieluszewska, Martyna Weglewska, Tomasz Bieluszewski, Krzysztof Lesniewicz, Elzbieta Poreba
The main function of the A kinase-anchoring proteins (AKAPs) is to target the cAMP-dependent protein kinase A (PKA) to its cellular substrates through the interaction with its regulatory subunits. Besides anchoring of PKA, AKAP8 participates in regulating the H3K4 histone methyltransferase (HMT) complexes. It is also involved in DNA replication, apoptosis, transcriptional silencing of rRNA genes, alternative splicing, and chromatin condensation during mitosis. In this study, we focused on the interaction between AKAP8 and the core subunit of all known H3K4 HMT complexes-DPY30 protein...
December 30, 2017: FEBS Journal
https://www.readbyqxmd.com/read/29288197/recruitment-and-allosteric-stimulation-of-a-histone-deubiquitinating-enzyme-during-heterochromatin-assembly
#8
Alexis Zukowksi, Nouf Omar Al-Afaleq, Emily D Duncan, Tingting Yao, Aaron M Johnson
Heterochromatin formation in budding yeast is regulated by the silent information regulator (SIR) complex. The SIR complex comprises the NAD-dependent deacetylase Sir2, the scaffolding protein Sir4, and the nucleosome-binding protein Sir3. Transcriptionally active regions present a challenge to SIR complex-mediated de novo heterochromatic silencing due to the presence of antagonistic histone PTMs, including acetylation and methylation. Methylation of histone H3K4 and H3K79 are dependent on mono-ubiquitination of histone H2B (H2B-Ub)...
December 29, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29282222/a-kdm5-inhibitor-increases-global-h3k4-trimethylation-occupancy-and-enhances-the-biological-efficacy-of-5-aza-2-deoxycytidine
#9
Benjamin R Leadem, Ioannis Kagiampakis, Catherine Wilson, Tommy K Cheung, David Arnott, Patrick Trojer, Marie Classon, Hariharan Easwaran, Stephen B Baylin
The H3K4 demethylase KDM5B is amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins (KDM5i), either alone or in combination with the DNA demethylating agent 5-aza-2'-deoxycytidine (DAC). KDM5i treatment alone increased expression of a small number of genes, whereas combined treatment with DAC enhanced the effects of the latter for increasing expression of hundreds of DAC-responsive genes...
December 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29281014/systematic-genetic-interaction-studies-identify-histone-demethylase-utx-as-potential-target-for-ameliorating-huntington-s-disease
#10
Wan Song, Nóra Zsindely, Anikó Faragó, J Lawrence Marsh, László Bodai
Huntington's Disease (HD) is a dominantly inherited neurodegenerative disease caused by alterations in the huntingtin gene (htt). Transcriptional dysregulation is an early event in HD progression. Protein acetylation and methylation particularly on histones regulates chromatin structure thereby preventing or facilitating transcription. Although protein acetylation has been found to affect HD symptoms, little is known about the potential role of protein methylation in HD pathology. In recent years, a series of proteins have been described that are responsible for methylating and demethylating histones as well as other proteins...
December 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29250818/trithorax-group-proteins-arabidopsis-trithorax4-atx4-and-atx5-function-in-abscisic-acid-and-dehydration-stress-responses
#11
Yutong Liu, Ai Zhang, Hao Yin, Qingxiang Meng, Xiaoming Yu, Shuangzhan Huang, Jie Wang, Rafiq Ahmad, Bao Liu, Zheng-Yi Xu
Trithorax-group proteins (TrxGs) play essential regulatory roles in chromatin modification to activate transcription. Although TrxGs have been shown to be extensively involved in the activation of developmental genes, how the specific TrxGs function in the dehydration and abscisic acid (ABA)-mediated modulation of downstream gene expression remains unknown. Here, we report that two evolutionarily conserved Arabidopsis thaliana TrxGs, ARABIDOPSIS TRITHORAX4 (ATX4) and ATX5, play essential roles in the drought stress response...
December 18, 2017: New Phytologist
https://www.readbyqxmd.com/read/29233090/dna-methylation-regulates-discrimination-of-enhancers-from-promoters-through-a-h3k4me1-h3k4me3-seesaw-mechanism
#12
Ali Sharifi-Zarchi, Daniela Gerovska, Kenjiro Adachi, Mehdi Totonchi, Hamid Pezeshk, Ryan J Taft, Hans R Schöler, Hamidreza Chitsaz, Mehdi Sadeghi, Hossein Baharvand, Marcos J Araúzo-Bravo
BACKGROUND: DNA methylation at promoters is largely correlated with inhibition of gene expression. However, the role of DNA methylation at enhancers is not fully understood, although a crosstalk with chromatin marks is expected. Actually, there exist contradictory reports about positive and negative correlations between DNA methylation and H3K4me1, a chromatin hallmark of enhancers. RESULTS: We investigated the relationship between DNA methylation and active chromatin marks through genome-wide correlations, and found anti-correlation between H3K4me1 and H3K4me3 enrichment at low and intermediate DNA methylation loci...
December 12, 2017: BMC Genomics
https://www.readbyqxmd.com/read/29212818/the-histone-demethylase-kdm5a-is-required-for-the-repression-of-astrocytogenesis-and-regulated-by-the-translational-machinery-in-neural-progenitor-cells
#13
Sun-Young Kong, Woosuk Kim, Ha-Rim Lee, Hyun-Jung Kim
Histone demethylases are known to play important roles in the determination of the fate of stem cells and in cancer progression. In this study, we show that the lysine 4 of histone H3 (H3K4), lysine-specific demethylase 5A (KDM5A) is essential for the repression of astrocyte differentiation in neural progenitor cells (NPCs), and its expression is regulated by translational machinery. Knockdown of KDM5A in NPCs increased astrocytogenesis, and conversely, KDM5A overexpression reduced the transcriptional activity of the Gfap promoter...
December 6, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29204143/local-chromatin-features-including-pu-1-and-ikaros-binding-and-h3k4-methylation-shape-the-repertoire-of-immunoglobulin-kappa-genes-chosen-for-v-d-j-recombination
#14
Louise S Matheson, Daniel J Bolland, Peter Chovanec, Felix Krueger, Simon Andrews, Hashem Koohy, Anne E Corcoran
V(D)J recombination is essential for the generation of diverse antigen receptor (AgR) repertoires. In B cells, immunoglobulin kappa (Igκ) light chain recombination follows immunoglobulin heavy chain (Igh) recombination. We recently developed the DNA-based VDJ-seq assay for the unbiased quantitation of Igh VH and DH repertoires. Integration of VDJ-seq data with genome-wide datasets revealed that two chromatin states at the recombination signal sequence (RSS) of VH genes are highly predictive of recombination in mouse pro-B cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29156705/upregulation-of-cd11b-and-cd86-through-lsd1-inhibition-promotes-myeloid-differentiation-and-suppresses-cell-proliferation-in-human-monocytic-leukemia-cells
#15
Jianwu Fang, Haiyan Ying, Ting Mao, Yanjia Fang, Yuan Lu, He Wang, Irene Zang, Zhaofu Wang, Ying Lin, Mengxi Zhao, Xiao Luo, Zongyao Wang, Yan Zhang, Chao Zhang, Wei Xiao, Yan Wang, Wei Tan, Zhui Chen, Chris Lu, Peter Atadja, En Li, Kehao Zhao, Jianfeng Liu, Justin Gu
LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in acute myeloid leukemia (AML) are not yet fully understood. Here, we report that small hairpin RNA (shRNA) mediated LSD1 inhibition causes a remarkable transcriptional activation of myeloid lineage marker genes (CD11b/ITGAM and CD86), reduction of cell proliferation and decrease of clonogenic ability of human AML cells...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29150847/chronic-sun-exposure-is-associated-with-distinct-histone-acetylation-changes-in-human-skin
#16
S Ding, J Chen, Q Zeng, J Lu, L Tan, A Guo, J Kang, S Yang, Y Xiang, C Zuo, J Huang
BACKGROUND: Photoaging is attributed to continuous sunlight or artificial UV exposure and manifests the clinical and histological changes of skin. Epigenetic changes have been found to be involved in the pathogenesis of photoaging. However, the underlying mechanisms are unclear. OBJECTIVES: To analyse histone modification patterns in sun-exposed and non-exposed skins, and identify the abnormally histone modified-genes related to photoaging. METHODS: Skin biopsies were collected both from the outer forearm (sun-exposed area) and the buttock (sun-protected area) in 20 healthy middle-aged female volunteers...
November 18, 2017: British Journal of Dermatology
https://www.readbyqxmd.com/read/29148585/arsenite-downregulates-h3k4-trimethylation-and-h3k9-dimethylation-during-transformation-of-human-bronchial-epithelial-cells
#17
Wei Tu, Yin Liu, Chengfeng Xie, Xue Zhou
Arsenic is an established human carcinogen but with weak mutagenic activity. The mechanisms of arsenic-induced carcinogenesis are not well understood. In the present study, we investigated the role of histone methylation in transformation of human bronchial epithelial (BEAS-2B) cells. After 16 weeks' exposure, cells were transformed by 0.1, 0.5 and 1 μm arsenite. Global trimethylated H3K4 (H3K4me3) was decreased by 0.1 μm arsenite at 12 weeks, and 0.5 and 1 μm arsenite at 8, 12 and 16 weeks, which could be attributed to reduced histone methyltransferase activities, increased histone demethylase (HDM) activities as well as increased protein levels of H3K4 demethylase KDM5A...
November 17, 2017: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/29142068/pharmacologic-inhibition-of-the-menin-mll-interaction-leads-to-transcriptional-repression-of-peg10-and-blocks-hepatocellular-carcinoma
#18
Katarzyna Kempinska, Bhavna Malik, Dmitry Borkin, Szymon Klossowski, Shirish Shukla, Hongzhi Miao, Jingya Wang, Tomasz Cierpicki, Jolanta Grembecka
Hepatocellular carcinoma (HCC) accounts for ~85% of malignant liver tumors and results in 600,000 deaths each year, emphasizing the need for new therapies. Upregulation of menin was reported in HCC patients and high levels of menin correlate with poor patient prognosis. The protein-protein interaction between menin and histone methyltransferase Mixed Lineage Leukemia 1 (MLL1) plays an important role in the development of HCC, implying that pharmacologic inhibition of this interaction could lead to new therapeutic strategy for the HCC patients...
November 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29138553/the-protective-effect-of-prmt6-overexpression-on-cigarette-smoke-extract-induced-murine-emphysema-model
#19
Xue He, Tiao Li, Naixin Kang, Huihui Zeng, Siying Ren, Dandan Zong, Jinhua Li, Shan Cai, Ping Chen, Yan Chen
Background: Cigarette smoke exposure is the most common risk factor for emphysema, which is one of the major pathologies of COPD. Protein arginine methyltransferase 6 (PRMT6) is a nuclear enzyme that specially catalyzes dimethylation of R2 in histone H3 (H3R2me2a). H3R2me2a prevents trimethylation of H3K4 (H3K4me3), which is located in the transcription start sites of genes in mammalian genomes. We attempted to determine the expression of PRMT6 in human samples, and investigate whether the upregulation of PRMT6 expression can attenuate the development of cigarette smoke extract (CSE)-induced emphysema...
2017: International Journal of Chronic Obstructive Pulmonary Disease
https://www.readbyqxmd.com/read/29137396/tgfbr-idh1-cav1-axis-promotes-tgf-%C3%AE-signalling-in-cancer-associated-fibroblast
#20
Xiaodan Hou, Jieying Zhang, Yongbin Wang, Wujun Xiong, Jun Mi
TGF-β signalling plays an important role in fibroblasts activation and tumour progression. Here, we report that the TGFBR-IDH1-Cav1 axis promotes TGF- β signalling in fibroblasts. Our data demonstrated that IDH1 was downregulated by TGF-β signalling in fibroblasts, and downregulation of IDH1 increased cellular concentration of α-ketoglutarate (α-KG) by accelerating glutamine metabolization. Interestingly, α-KG suppressed Cav1 expression through reducing the trimethylation of histone H3K4. Furthermore, Cav1 downregulation inhibited TGFBR protein degradation...
October 13, 2017: Oncotarget
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