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https://www.readbyqxmd.com/read/28803780/methylation-of-dna-ligase-1-by-g9a-glp-recruits-uhrf1-to-replicating-dna-and-regulates-dna-methylation
#1
Laure Ferry, Alexandra Fournier, Takeshi Tsusaka, Guillaume Adelmant, Tadahiro Shimazu, Shohei Matano, Olivier Kirsh, Rachel Amouroux, Naoshi Dohmae, Takehiro Suzuki, Guillaume J Filion, Wen Deng, Maud de Dieuleveult, Lauriane Fritsch, Srikanth Kudithipudi, Albert Jeltsch, Heinrich Leonhardt, Petra Hajkova, Jarrod A Marto, Kyohei Arita, Yoichi Shinkai, Pierre-Antoine Defossez
DNA methylation is an essential epigenetic mark in mammals that has to be re-established after each round of DNA replication. The protein UHRF1 is essential for this process; it has been proposed that the protein targets newly replicated DNA by cooperatively binding hemi-methylated DNA and H3K9me2/3, but this model leaves a number of questions unanswered. Here, we present evidence for a direct recruitment of UHRF1 by the replication machinery via DNA ligase 1 (LIG1). A histone H3K9-like mimic within LIG1 is methylated by G9a and GLP and, compared with H3K9me2/3, more avidly binds UHRF1...
August 4, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28791163/nonlinear-disease-tolerance-curves-reveal-distinct-components-of-host-responses-to-viral-infection
#2
Vanika Gupta, Pedro F Vale
The ability to tolerate infection is a key component of host defence and offers potential novel therapeutic approaches for infectious diseases. To yield successful targets for therapeutic intervention, it is important that the analytical tools employed to measure disease tolerance are able to capture distinct host responses to infection. Here, we show that commonly used methods that estimate tolerance as a linear relationship should be complemented with more flexible, nonlinear estimates of this relationship which may reveal variation in distinct components such as host vigour, sensitivity to increases in pathogen loads, and the severity of the infection...
July 2017: Royal Society Open Science
https://www.readbyqxmd.com/read/28791052/inhibition-of-histone-methyltransferase-histone-deacetylase-and-%C3%AE-catenin-synergistically-enhance-the-cardiac-potential-of-bone-marrow-cells
#3
Jinpu Yang, Keerat Kaur, John G Edwards, Carol A Eisenberg, Leonard M Eisenberg
Previously, we reported that treatment with the G9a histone methyltransferase inhibitor BIX01294 causes bone marrow mesenchymal stem cells (MSCs) to exhibit a cardiocompetent phenotype, as indicated by the induction of the precardiac markers Mesp1 and brachyury. Here, we report that combining the histone deacetylase inhibitor trichostatin A (TSA) with BIX01294 synergistically enhances MSC cardiogenesis. Although TSA by itself had no effect on cardiac gene expression, coaddition of TSA to MSC cultures enhanced BIX01294-induced levels of Mesp1 and brachyury expression 5...
2017: Stem Cells International
https://www.readbyqxmd.com/read/28778076/modulation-of-the-fanconi-anemia-pathway-via-chemically-induced-changes-in-chromatin-structure
#4
David A Vierra, Jada L Garzon, Meghan A Rego, Morganne M Adroved, Maurizio Mauro, Niall G Howlett
Fanconi anemia (FA) is a rare disease characterized by congenital defects, bone marrow failure, and atypically early-onset cancers. The FA proteins function cooperatively to repair DNA interstrand crosslinks. A major step in the activation of the pathway is the monoubiquitination of the FANCD2 and FANCI proteins, and their recruitment to chromatin-associated nuclear foci. The regulation and function of FANCD2 and FANCI, however, is poorly understood. In addition, how chromatin state impacts pathway activation is also unknown...
July 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28765096/effects-of-bpa-on-global-dna-methylation-and-global-histone-3-lysine-modifications-in-sh-sy5y-cells-an-epigenetic-mechanism-linking-the-regulation-of-chromatin-modifiying-genes
#5
Mine Senyildiz, Ecem Fatma Karaman, Serap Sancar Bas, Pelin Arda Pirincci, Sibel Ozden
Bisphenol A (BPA), an estrogenic endocrine disruptor, is widely used in the production of polycarbonate plastic and epoxy resins, resulting in high risk on human health. In present study we aimed to investigate the effects of BPA on global and gene specific DNA methylation, global histone modifications and regulation of chromatin modifiying enzymes in human neuroblastoma cells (SH-SY5Y). Cells were treated with BPA at 0.1, 1 and 10μM concentrations for 48 and 96h. IC50 value of BPA was determined as 183 and 129μM in SH-SY5Y cells after 24h by MTT and NRU tests, respectively...
July 29, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28723643/methyltransferase-g9a-promotes-cervical-cancer-angiogenesis-and-decreases-patient-survival
#6
Ruey-Jien Chen, Chia-Tung Shun, Men-Luh Yen, Chia-Hung Chou, Ming-Chieh Lin
Research suggests that the epigenetic regulator G9a, a H3K9 histone methyltransferase, is involved in cancer invasion and metastasis. Here we show that G9a is linked to cancer angiogenesis and poor patient survival. Invasive cervical cancer has a higher G9a expression than cancer precursors or normal epithelium. Pharmacological inhibition and genetic silencing of G9a suppresses H3K9 methylation, cancer cell proliferation, angiogenesis, and cancer cell invasion/migration, but not apoptosis. Microarray and quantitative reverse transcription polymerase chain reaction analyses reveal that G9a induces a cohort of angiogenic factors that include angiogenin, interleukin-8, and C-X-C motif chemokine ligand 16...
July 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28706131/structure-based-design-synthesis-and-activity-studies-of-small-hybrid-molecules-as-hdac-and-g9a-dual-inhibitors
#7
Lanlan Zang, Shukkoor M Kondengaden, Qing Zhang, Xiaobo Li, Dilep K Sigalapalli, Shameer M Kondengadan, Kenneth Huang, Keqin Kathy Li, Shanshan Li, Zhongying Xiao, Liuqing Wen, Hailiang Zhu, Bathini N Babu, Lijuan Wang, Fengyuan Che, Peng George Wang
Aberrant enzymatic activities or expression profiles of epigenetic regulations are therapeutic targets for cancers. Among these, histone 3 lysine 9 methylation (H3K9Me2) and global de-acetylation on histone proteins are associated with multiple cancer phenotypes including leukemia, prostatic carcinoma, hepatocellular carcinoma and pulmonary carcinoma. Here, we report the discovery of the first small molecule capable of acting as a dual inhibitor targeting both G9a and HDAC. Our structure based design, synthesis, and screening for the dual activity of the small molecules led to the discovery of compound 14 which displays promising inhibition of both G9a and HDAC in low micro-molar range in cell based assays...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28698370/g9a-coordinates-with-the-rpa-complex-to-promote-dna-damage-repair-and-cell-survival
#8
Qiaoyan Yang, Qian Zhu, Xiaopeng Lu, Yipeng Du, Linlin Cao, Changchun Shen, Tianyun Hou, Meiting Li, Zhiming Li, Chaohua Liu, Di Wu, Xingzhi Xu, Lina Wang, Haiying Wang, Ying Zhao, Yang Yang, Wei-Guo Zhu
Histone methyltransferase G9a has critical roles in promoting cancer-cell growth and gene suppression, but whether it is also associated with the DNA damage response is rarely studied. Here, we report that loss of G9a impairs DNA damage repair and enhances the sensitivity of cancer cells to radiation and chemotherapeutics. In response to DNA double-strand breaks (DSBs), G9a is phosphorylated at serine 211 by casein kinase 2 (CK2) and recruited to chromatin. The chromatin-enriched G9a can then directly interact with replication protein A (RPA) and promote loading of the RPA and Rad51 recombinase to DSBs...
July 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28698219/the-transcription-factor-c-ebp%C3%AE-in-the-dorsal-root-ganglion-contributes-to-peripheral-nerve-trauma-induced-nociceptive-hypersensitivity
#9
Zhisong Li, Yuanyuan Mao, Lingli Liang, Shaogen Wu, Jingjing Yuan, Kai Mo, Weihua Cai, Qingxiang Mao, Jing Cao, Alex Bekker, Wei Zhang, Yuan-Xiang Tao
Changes in gene transcription in the dorsal root ganglion (DRG) after nerve trauma contribute to the genesis of neuropathic pain. We report that peripheral nerve trauma caused by chronic constriction injury (CCI) increased the abundance of the transcription factor C/EBPβ (CCAAT/enhancer binding protein β) in the DRG. Blocking this increase mitigated the development and maintenance of CCI-induced mechanical, thermal, and cold pain hypersensitivities without affecting basal responses to acute pain and locomotor activity...
July 11, 2017: Science Signaling
https://www.readbyqxmd.com/read/28677817/inhibition-of-the-hdac-suv39-g9a-pathway-restores-the-expression-of-dna-damage-dependent-major-histocompatibility-complex-class%C3%A2-i-related-chain%C3%A2-a%C3%A2-and%C3%A2-b-in-cancer-cells
#10
Nakako Izumi Nakajima, Atsuko Niimi, Mayu Isono, Takahiro Oike, Hiro Sato, Takashi Nakano, Atsushi Shibata
Immunotherapy is expected to be promising as a next generation cancer therapy. Immunoreceptors are often activated constitutively in cancer cells, however, such levels of ligand expression are not effectively recognized by the native immune system due to tumor microenvironmental adaptation. Studies have demonstrated that natural-killer group 2, member D (NKG2D), a major activating immunoreceptor, responds to DNA damage. The upregulation of major histocompatibility complex class I-related chain A and B (MICA/B) (members of NKG2D ligands) expression after DNA damage is associated with NK cell-mediated killing of cancer cells...
June 30, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28667416/satb2-suppresses-non-small-cell-lung-cancer-invasiveness-by-g9a
#11
Yi-Nan Ma, Hai-Yan Zhang, Liang-Ru Fei, Mei-Yu Zhang, Cong-Cong Wang, Yuan Luo, Yu-Chen Han
Special AT-rich sequence-binding protein 2 (SATB2) is a transcription factor, which plays an important role in transcriptional regulation and chromatin recombinant by combining with matrix attachment regions. More evidence shows that SATB2 is involved in progression of breast cancer, head and neck squamous cell carcinomas and osteosarcoma. However, the role of SATB2 in cancer initiation and progression is still not well understood. Our study identified that decreased expression of SATB2 was correlated with tumor progression and poor prognosis in non-small cell lung cancer (NSCLC) patients...
June 30, 2017: Clinical and Experimental Medicine
https://www.readbyqxmd.com/read/28665013/epigenetic-regulation-by-g9a-glp-complex-ameliorates-amyloid-beta-1-42-induced-deficits-in-long-term-plasticity-and-synaptic-tagging-capture-in-hippocampal-pyramidal-neurons
#12
Mahima Sharma, Tobias Dierkes, Sreedharan Sajikumar
Altered epigenetic mechanisms are implicated in the cognitive decline associated with neurodegenerative diseases such as in Alzheimer's disease (AD). AD is the most prevalent form of dementia worldwide; amyloid plaques and neurofibrillary tangles are the histopathological hallmarks of AD. We have recently reported that the inhibition of G9a/GLP complex promotes long-term potentiation (LTP) and its associative mechanisms such as synaptic tagging and capture (STC). However, the role of this complex in plasticity impairments remains elusive...
June 30, 2017: Aging Cell
https://www.readbyqxmd.com/read/28662962/structure-activity-relationship-studies-of-g9a-like-protein-glp-inhibitors
#13
Yan Xiong, Fengling Li, Nicolas Babault, Hong Wu, Aiping Dong, Hong Zeng, Xin Chen, Cheryl H Arrowsmith, Peter J Brown, Jing Liu, Masoud Vedadi, Jian Jin
Given the high homology between the protein lysine methyltransferases G9a-like protein (GLP) and G9a, it has been challenging to develop potent and selective inhibitors for either enzyme. Recently, we reported two quinazoline compounds, MS0124 and MS012, as GLP selective inhibitors. To further investigate the structure-activity relationships (SAR) of the quinazoline scaffold, we designed and synthesized a range of analogs bearing different 2-amino substitutions and evaluated their inhibition potencies against both GLP and G9a...
August 15, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28655069/delivery-of-parasite-cdg7_flc_0990-rna-transcript-into-intestinal-epithelial-cells-during-cryptosporidium-parvum-infection-suppresses-host-cell-gene-transcription-through-epigenetic-mechanisms
#14
Yang Wang, Ai-Yu Gong, Shibin Ma, Xiqiang Chen, Juliane K Strauss-Soukup, Xian-Ming Chen
Cryptosporidial infection causes dysregulated transcription of host genes key to intestinal epithelial homeostasis, but the underlying mechanisms remain obscure. Previous studies demonstrate that several C. parvum RNA transcripts are selectively delivered into epithelial cells during host cell invasion and may modulate gene transcription in infected cells. We report here that C. parvum infection suppresses the transcription of LRP5, SLC7A8, and IL33 genes in infected intestinal epithelium. Trans-suppression of these genes in infected host cells is associated with promoter enrichment of suppressive epigenetic markers (i...
June 27, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/28644763/methyltransferase-g9a-regulates-osteogenesis-via-twist-gene-repression
#15
N Higashihori, B Lehnertz, A Sampaio, T M Underhill, F Rossi, J M Richman
Here we investigate the role of epigenetic factors in controlling the timing of cranial neural crest cell differentiation. The gene coding for histone H3 lysine 9 methyltransferase G9A was conditionally deleted in neural crest cells with Wnt1-Cre. The majority of homozygous-null animals survived to birth but thereafter failed to thrive. Phenotypic analysis of postnatal animals revealed that the mutants displayed incomplete ossification and 20% shorter jaws as compared to their wild-type littermates. At E13...
June 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28641467/green-tea-polyphenol-egcg-causes-anti-cancerous-epigenetic-modulations-in-acute-promyelocytic-leukemia-cells
#16
Veronika Borutinskaitė, Aida Virkšaitė, Giedrė Gudelytė, Rūta Navakauskienė
Green tea (Camellia sinensis) catechin epigallocatechin-3-gallate (EGCG) has been shown to possess diverse anti-cancerous properties. We demonstrated EGCG ability to inhibit acute promyelocytic leukemia (APL) cell proliferation and cause apoptosis. In addition, quantitative real-time polymerase chain reaction (RT-qPCR) analysis revealed elevated expression of genes associated with cell cycle arrest and differentiation (p27, PCAF, C/EBPα, and C/EBPɛ). Furthermore, EGCG caused anti-cancerous epigenetic changes: downregulation of epigenetic modifiers DNMT1, HDAC1, HDAC2, and G9a was observed by RT-qPCR analysis...
June 22, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28630300/g9a-drives-hypoxia-mediated-gene-repression-for-breast-cancer-cell-survival-and-tumorigenesis
#17
Francesco Casciello, Fares Al-Ejeh, Greg Kelly, Donal J Brennan, Shin Foong Ngiow, Arabella Young, Thomas Stoll, Karolina Windloch, Michelle M Hill, Mark J Smyth, Frank Gannon, Jason S Lee
G9a is an epigenetic regulator that methylates H3K9, generally causing repression of gene expression, and participates in diverse cellular functions. G9a is genetically deregulated in a variety of tumor types and can silence tumor suppressor genes and, therefore, is important for carcinogenesis. Although hypoxia is recognized to be an adverse factor in tumor growth and metastasis, the role of G9a in regulating gene expression in hypoxia has not been described extensively. Here, we show that G9a protein stability is increased in hypoxia via reduced proline hydroxylation and, hence, inefficient degradation by the proteasome...
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28615290/a-post-translational-modification-switch-controls-coactivator-function-of-histone-methyltransferases-g9a-and-glp
#18
Coralie Poulard, Danielle Bittencourt, Dai-Ying Wu, Yixin Hu, Daniel S Gerke, Michael R Stallcup
Like many transcription regulators, histone methyltransferases G9a and G9a-like protein (GLP) can act gene-specifically as coregulators, but mechanisms controlling this specificity are mostly unknown. We show that adjacent post-translational methylation and phosphorylation regulate binding of G9a and GLP to heterochromatin protein 1 gamma (HP1γ), formation of a ternary complex with the glucocorticoid receptor (GR) on chromatin, and function of G9a and GLP as coactivators for a subset of GR target genes. HP1γ is recruited by G9a and GLP to GR binding sites associated with genes that require G9a, GLP, and HP1γ for glucocorticoid-stimulated transcription...
August 2017: EMBO Reports
https://www.readbyqxmd.com/read/28599414/g9a-performs-important-roles-in-the-progression-of-breast-cancer-through-upregulating-its-targets
#19
Wenhua Jiang, Pengfei Liu, Xiaodong Li
Breast cancer (BC) is the most common type of malignancy in females worldwide, however, its underlying mechanisms remain poorly understood. The present study aimed to investigate the mechanisms behind the development and progression of BC and identify potential biomarkers for it. The chromatin immunoprecipitation-DNA sequencing (ChIP-Seq) dataset GSM1642516 and gene expression dataset GSE34925 were downloaded from the Gene Expression Omnibus database. Affy and oligo packages were used for the background correction and normalization of the gene expression dataset...
June 2017: Oncology Letters
https://www.readbyqxmd.com/read/28596979/the-expanding-role-of-the-ehmt2-g9a-complex-in-neurodevelopment
#20
COMMENT
Steven J Deimling, Jonathan B Olsen, Vincent Tropepe
Epigenetic regulators play a crucial role in neurodevelopment. One such epigenetic complex, Ehmt1/2 (G9a/GLP), is essential for repressing gene transcription by methylating H3K9 in a highly tissue- and temporal-specific manner. Recently, data has emerged suggesting that this complex plays additional roles in regulating the activity of numerous other non-histone proteins. While much is known about the downstream effects of Ehmt1/2 function, evidence is only beginning to come to light suggesting the control of Ehmt1/2 function may be, at least in part, due to context-dependent binding partners...
2017: Neurogenesis (Austin, Tex.)
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