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https://www.readbyqxmd.com/read/28228401/wolf-hirschhorn-syndrome-candidate-1-like-1-epigenetically-regulates-nephrin-gene-expression
#1
Yugo Ito, Kan Katayama, Yukino Nishibori, Yoshihiro Akimoto, Akihiko Kudo, Ryota Kurayama, Ichiro Hada, Shohei Takahashi, Toru Kimura, Toshiyuki Fukutomi, Tomohisa Katada, Junichi Suehiro, Olga Beltcheva, Karl Tryggvason, Kunimasa Yan
Altered expression of nephrin underlies the pathophysiology of proteinuria in both congenital and acquired nephrotic syndrome. However, the epigenetic mechanisms of nephrin gene regulation remain elusive. Here, we show that Wolf-Hirschhorn syndrome candidate 1-like 1 long form (WHSC1L1-L) is a novel epigenetic modifier of nephrin gene regulation. WHSC1L1-L was associated with histone H3K4 and H3K36 in human embryonic kidney cells. WHSC1L1-L gene was expressed in the podocytes and functional protein product was detected in these cells...
February 22, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28223829/cul4a-promotes-proliferation-and-metastasis-of-colorectal-cancer-cells-by-regulating-h3k4-trimethylation-in-epithelial-mesenchymal-transition
#2
Xuemei Sui, Hong Zhou, Lei Zhu, Deqiang Wang, Sumei Fan, Wei Zhao
Increasing evidence suggests that CUL4A, a ubiquitin ligase, is involved in the promotion of cancer malignancy and correlated with worse clinical prognosis in several kinds of human cancers. Although its effect and mechanism on the progression of colorectal cancer (CRC) remain unknown. Our clinical data show that CUL4A protein is overexpressed, positively associated with lymph nodes status, differentiation degree, tumor size, and poor prognosis in 80 CRC patients. CUL4A overexpression promotes cell proliferation and colony formation of CRC cells...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28216155/forced-fog1-expression-in-erythroleukemia-cells-induction-of-erythroid-genes-and-repression-of-myelo-lymphoid-transcription-factor-pu-1
#3
Tohru Fujiwara, Katsuyuki Sasaki, Kei Saito, Shunsuke Hatta, Satoshi Ichikawa, Masahiro Kobayashi, Yoko Okitsu, Noriko Fukuhara, Yasushi Onishi, Hideo Harigae
The transcription factor GATA-1-interacting protein Friend of GATA-1 (FOG1) is essential for proper transcriptional activation and repression of GATA-1 target genes; yet, the mechanisms by which FOG1 exerts its activating and repressing functions remain unknown. Forced FOG1 expression in human K562 erythroleukemia cells induced the expression of erythroid genes (SLC4A1, globins) but repressed that of GATA-2 and PU.1. A quantitative chromatin immunoprecipitation (ChIP) analysis demonstrated increased GATA-1 chromatin occupancy at both FOG1-activated as well as FOG1-repressed gene loci...
February 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28194553/acidic-domains-differentially-read-histone-h3-lysine-4-methylation-status-and-are-widely-present-in-chromatin-associated-proteins
#4
Meng Wu, Wei Wei, Jiwei Chen, Rong Cong, Tieliu Shi, Jiwen Li, Jiemin Wong, James X Du
Histone methylation is believed to provide binding sites for specific reader proteins, which translate histone code into biological function. Here we show that a family of acidic domain-containing proteins including nucleophosmin (NPM1), pp32, SET/TAF1β, nucleolin (NCL) and upstream binding factor (UBF) are novel H3K4me2-binding proteins. These proteins exhibit a unique pattern of interaction with methylated H3K4, as their binding is stimulated by H3K4me2 and inhibited by H3K4me1 and H3K4me3. These proteins contain one or more acidic domains consisting mainly of aspartic and/or glutamic residues that are necessary for preferential binding of H3K4me2...
February 13, 2017: Science China. Life Sciences
https://www.readbyqxmd.com/read/28186757/thieno-3-2-b-pyrrole-5-carboxamides-as-new-reversible-inhibitors-of-histone-lysine-demethylase-kdm1a-lsd1-part-2-structure-based-drug-design-and-structure-activity-relationship
#5
Paola Vianello, Luca Sartori, Federica Amigoni, Anna Cappa, Giovanni Fagá, Raimondo Fattori, Elena Legnaghi, Giuseppe Ciossani, Andrea Mattevi, Giuseppe Meroni, Loris Moretti, Valentina Cecatiello, Sebastiano Pasqualato, Alessia Romussi, Florian Thaler, Paolo Trifiró, Oronza A Botrugno, Manuela Villa, Paola Dessanti, Saverio Minucci, Stefania Vultaggio, Elisa Zagarrí, Mario Varasi, Ciro Mercurio
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described (Part 1) the identification of thieno[3,2-b]pyrrole-5-carboxamides, as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series, based on multiple ligand/KDM1A-CoRest co-crystal structures, which led to several extremely potent inhibitors...
February 10, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28185526/low-expression-of-ash2l-protein-correlates-with-a-favorable-outcome-in-acute-myeloid-leukemia
#6
Jill S Butler, Yi Hua Qiu, Nianxiang Zhang, Suk-Young Yoo, Kevin R Coombes, Sharon Y R Dent, Steven M Kornblau
ASH2L encodes a trithorax group protein that is a core component of all characterized mammalian histone H3K4 methyltransferase complexes, including mixed lineage leukemia (MLL) complexes. ASH2L protein levels in primary leukemia patient samples have not yet been defined. We analyzed ASH2L protein expression in 511 primary AML patient samples using reverse phase protein array (RPPA) technology. We discovered that ASH2L expression is significantly increased in a subset of patients carrying fms-related tyrosine kinase 3 (FLT3) mutations...
May 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28182322/somatic-cancer-mutations-in-the-mll1-histone-methyltransferase-modulate-its-enzymatic-activity-and-dependence-on-the-wdr5-rbbp5-ash2l-complex
#7
Sara Weirich, Srikanth Kudithipudi, Albert Jeltsch
Somatic missense mutations in the MLL1 histone H3K4 methyltransferase are often observed in cancers. MLL1 forms a complex with WDR5, RBBP5 and ASH2L (WRA) which stimulates its activity. The MM-102 compound prevents the interaction between MLL1 and WDR5 and functions as an MLL1 inhibitor. We have studied the effects of four cancer mutations in the catalytic SET domain of MLL1 on the enzymatic activity of MLL1 and MLL1-WRA complexes. In addition, we studied the interaction of the MLL1 mutants with the WRA proteins and inhibition of MLL1-WRA complexes by MM-102...
February 9, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28158205/structure-activity-relationship-and-modeling-studies-of-inhibitors-of-lysine-specific-demethylase-1
#8
Chao Zhou, Fangrui Wu, Lianghao Lu, Liping Wei, Eric Pai, Yuan Yao, Yongcheng Song
Post-translational modifications of histone play important roles in gene transcription. Aberrant methylation of histone lysine sidechains have been often found in cancer. Lysine specific demethylase 1 (LSD1), which can demethylate histone H3 lysine 4 (H3K4) and other proteins, has recently been found to be a drug target for acute myeloid leukemia. To understand structure activity/selectivity relationships of LSD1 inhibitors, several series of cyclopropylamine and related compounds were synthesized and tested for their activities against LSD1 and related monoamine oxidase (MAO) A and B...
2017: PloS One
https://www.readbyqxmd.com/read/28157506/not-all-h3k4-methylations-are-created-equal-mll2-compass-dependency-in-primordial-germ-cell-specification
#9
Deqing Hu, Xin Gao, Kaixiang Cao, Marc A Morgan, Gloria Mas, Edwin R Smith, Andrew G Volk, Elizabeth T Bartom, John D Crispino, Luciano Di Croce, Ali Shilatifard
The spatiotemporal regulation of gene expression is central for cell-lineage specification during embryonic development and is achieved through the combinatorial action of transcription factors/co-factors and epigenetic states at cis-regulatory elements. Here, we show that in addition to implementing H3K4me3 at promoters of bivalent genes, Mll2 (KMT2B)/COMPASS can also implement H3K4me3 at a subset of non-TSS regulatory elements, a subset of which shares epigenetic signatures of active enhancers. Our mechanistic studies reveal that association of Mll2's CXXC domain with CpG-rich regions plays an instrumental role for chromatin targeting and subsequent implementation of H3K4me3...
February 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28152483/lsd1-collaborates-with-ezh2-to-regulate-expression-of-interferon-stimulated-genes
#10
Yue Jin, Bo Huo, Xueqi Fu, Tian Hao, Yu Zhang, Yidi Guo, Xin Hu
Histone methylation is a complicate and dynamic epigenetic modification that regulates gene transcription, chromosomal structure and cell differentiation. Here, we discovered the interaction between the H3K4 demethylase, lysine specific demethylase 1 (LSD1, an important component of CoREST repressor complex) and the H3K27 methyltransferase, enhancer of zeste homolog 2 (EZH2, an essential component of PRC2). Immuno-precipitation and GST-pull down assay were performed to observe the interaction between the proteins...
January 30, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28143781/phenformin-enhances-the-efficacy-of-erk-inhibition-in-nf1-mutant-melanoma
#11
Sebastian Trousil, Shuang Chen, Chan Mu, Fiona M Shaw, Zhan Yao, Yuping Ran, Tiwari Shakuntala, Taha Merghoub, Dieter Manstein, Neal Rosen, Lewis C Cantley, Jonathan H Zippin, Bin Zheng
Inactivation of the tumor suppressor neurofibromin 1 (NF1) presents a newly characterized melanoma subtype, for which currently no targeted therapies are clinically available. Pre-clinical studies suggest that ERK inhibitors are likely to provide benefit, albeit with limited efficacy as single agent; therefore, there is a need for rationally designed combination therapies. Here, we evaluate the combination of the ERK inhibitor SCH772984 and the biguanide phenformin. Combination of both compounds showed potent synergy in cell viability assays and cooperatively induced apoptosis...
January 28, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28137832/chromatin-potentiates-transcription
#12
Shigeki Nagai, Ralph E Davis, Pierre Jean Mattei, Kyle Patrick Eagen, Roger D Kornberg
Chromatin isolated from the chromosomal locus of the PHO5 gene of yeast in a transcriptionally repressed state was transcribed with 12 pure proteins (80 polypeptides): RNA polymerase II, six general transcription factors, TFIIS, the Pho4 gene activator protein, and the SAGA, SWI/SNF, and Mediator complexes. Contrary to expectation, a nucleosome occluding the TATA box and transcription start sites did not impede transcription but rather, enhanced it: the level of chromatin transcription was at least sevenfold greater than that of naked DNA, and chromatin gave patterns of transcription start sites closely similar to those occurring in vivo, whereas naked DNA gave many aberrant transcripts...
January 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28131992/the-mll1-h3k4me3-axis-mediated-pd-l1-expression-and-pancreatic-cancer-immune-evasion
#13
Chunwan Lu, Amy V Paschall, Huidong Shi, Natasha Savage, Jennifer L Waller, Maria E Sabbatini, Nicholas H Oberlies, Cedric Pearce, Kebin Liu
BACKGROUND: Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion. METHODS: Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion...
January 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28125013/involvement-of-fvset1-in-fumonisin-b1-biosynthesis-vegetative-growth-fungal-virulence-and-environmental-stress-responses-in-fusarium-verticillioides
#14
Qin Gu, Hafiz Abdul Samad Tahir, Hao Zhang, Hai Huang, Tiantian Ji, Xiao Sun, Liming Wu, Huijun Wu, Xuewen Gao
Fusarium verticillioides (teleomorph, Gibberella moniliformis) is an important plant pathogen that causes seedling blight, stalk rot, and ear rot in maize (Zea mays). During infection, F. verticillioides produce fumonsins B1 (FB1) that pose a serious threat to human and animal health. Recent studies showed that Set1, a methyltransferase of H3K4, was responsible for toxin biosynthesis in filamentous fungi. However, to date, the regulation of FvSet1 on FB1 biosynthesis remains unclear. In the current study, we identified only one Set1 ortholog in F...
January 24, 2017: Toxins
https://www.readbyqxmd.com/read/28121627/identification-of-downstream-metastasis-associated-target-genes-regulated-by-lsd1-in-colon-cancer-cells
#15
Jiang Chen, Jie Ding, Ziwei Wang, Jian Zhu, Xuejian Wang, Jiyi Du
PURPOSE: This study aims to identify downstream target genes regulated by lysine-specific demethylase 1 (LSD1) in colon cancer cells and investigate the molecular mechanisms of LSD1 influencing invasion and metastasis of colon cancer. METHOD: We obtained the expression changes of downstream target genes regulated by small-interfering RNA-LSD1 and LSD1-overexpression via gene expression profiling in two human colon cancer cell lines. An Affymetrix Human Transcriptome Array 2...
January 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28115742/mef2c-transcription-factor-is-associated-with-the-genetic-and-epigenetic-risk-architecture-of-schizophrenia-and-improves-cognition-in-mice
#16
A C Mitchell, B Javidfar, V Pothula, D Ibi, E Y Shen, C J Peter, L K Bicks, T Fehr, Y Jiang, K J Brennand, R L Neve, J Gonzalez-Maeso, S Akbarian
Large-scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report myocyte enhancer factor 2C (MEF2C) motif enrichment in sequences surrounding the top scoring single-nucleotide polymorphisms within risk loci contributing by individual small effect to disease heritability. Chromatin profiling at base-pair resolution in neuronal nucleosomes extracted from prefrontal cortex of 34 subjects, including 17 cases diagnosed with schizophrenia, revealed MEF2C motif enrichment within cis-regulatory sequences, including neuron-specific promoters and superenhancers, affected by histone H3K4 hypermethylation in disease cases...
January 24, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28113136/tumor-necrosis-factor-alpha-inhibitors-suppress-ccl2-chemokine-in-monocytes-via-epigenetic-modification
#17
Yi-Ching Lin, Yu-Chih Lin, Ming-Yii Huang, Po-Lin Kuo, Cheng-Chin Wu, Min-Sheng Lee, Chong-Chao Hsieh, Hsuan-Fu Kuo, Chang-Hung Kuo, Wen-Chan Tsai, Chih-Hsing Hung
The treatment of rheumatoid arthritis (RA) with tumor necrosis factor-alpha (TNF-α) inhibitors could lead to adverse effects. Therefore, the identification of downstream therapeutic targets is important. Monocyte chemoattractant protein-1 (MCP-1, also called CCL2) is related to RA disease activity, and epigenetic modifications are hypothesized to regulate gene expression in RA pathogenesis. We studied the effects of two TNF-α inhibitors, etanercept and adalimumab, on CCL2 expression and the potentially associated intracellular mechanisms, including epigenetic regulation...
March 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28108585/histone-h3k4-and-h3k36-methylation-independently-recruit-the-nua3-histone-acetyltransferase-in-saccharomyces-cerevisiae
#18
Benjamin J E Martin, Kristina L McBurney, Vicki E Maltby, Kristoffer N Jensen, Julie Brind'Amour, LeAnn Howe
Histone post-translational modifications (PTMs) alter chromatin structure by promoting the interaction of chromatin-modifying complexes with nucleosomes. The majority of chromatin-modifying complexes contain multiple domains that preferentially interact with modified histones, leading to speculation that these domains function in concert to target nucleosomes with distinct combinations of histone PTMs. In S. cerevisiae, the NuA3 histone acetyltransferase complex contains three domains, the PHD finger in Yng1, the PWWP domain in Pdp3, and the YEATS domain in Taf14, which in vitro bind to H3K4 methylation, H3K36 methylation, and acetylated and crotonylated H3K9 respectively...
January 20, 2017: Genetics
https://www.readbyqxmd.com/read/28100676/gene-body-chromatin-modification-dynamics%C3%A2-mediate-epigenome-differentiation-in%C3%A2-arabidopsis
#19
Soichi Inagaki, Mayumi Takahashi, Aoi Hosaka, Tasuku Ito, Atsushi Toyoda, Asao Fujiyama, Yoshiaki Tarutani, Tetsuji Kakutani
Heterochromatin is marked by methylation of lysine 9 on histone H3 (H3K9me). A puzzling feature of H3K9me is that this modification localizes not only in promoters but also in internal regions (bodies) of silent transcription units. Despite its prevalence, the biological significance of gene-body H3K9me remains enigmatic. Here we show that H3K9me-associated removal of H3K4 monomethylation (H3K4me1) in gene bodies mediates transcriptional silencing. Mutations in an Arabidopsis H3K9 demethylase gene IBM1 induce ectopic H3K9me2 accumulation in gene bodies, with accompanying severe developmental defects...
January 18, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28096401/ornithine-decarboxylase-regulates-m1-macrophage-activation-and-mucosal-inflammation-via-histone-modifications
#20
Dana M Hardbower, Mohammad Asim, Paula B Luis, Kshipra Singh, Daniel P Barry, Chunying Yang, Meredith A Steeves, John L Cleveland, Claus Schneider, M Blanca Piazuelo, Alain P Gobert, Keith T Wilson
Macrophage activation is a critical step in host responses during bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine metabolism, has been well studied in epithelial cells and is known to have essential roles in many different cellular functions. However, its role in regulating macrophage function during bacterial infections is not well characterized. We demonstrate that macrophage-derived ODC is a critical regulator of M1 macrophage activation during both Helicobacter pylori and Citrobacter rodentium infection...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
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