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https://www.readbyqxmd.com/read/28102363/smarca4-inactivating-mutations-increase-sensitivity-to-aurora-kinase-a-inhibitor-vx-680-in-non-small-cell-lung-cancers
#1
Vural Tagal, Shuguang Wei, Wei Zhang, Rolf A Brekken, Bruce A Posner, Michael Peyton, Luc Girard, TaeHyun Hwang, David A Wheeler, John D Minna, Michael A White, Adi F Gazdar, Michael G Roth
Mutations in the SMARCA4/BRG1 gene resulting in complete loss of its protein (BRG1) occur frequently in non-small cell lung cancer (NSCLC) cells. Currently, no single therapeutic agent has been identified as synthetically lethal with SMARCA4/BRG1 loss. We identify AURKA activity as essential in NSCLC cells lacking SMARCA4/BRG1. In these cells, RNAi-mediated depletion or chemical inhibition of AURKA induces apoptosis and cell death in vitro and in xenograft mouse models. Disc large homologue-associated protein 5 (HURP/DLGAP5), required for AURKA-dependent, centrosome-independent mitotic spindle assembly is essential for the survival and proliferation of SMARCA4/BRG1 mutant but not of SMARCA4/BRG1 wild-type cells...
January 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/28091529/long-non-coding-rna-linc-ram-enhances-myogenic-differentiation-by-interacting-with-myod
#2
Xiaohua Yu, Yong Zhang, Tingting Li, Zhao Ma, Haixue Jia, Qian Chen, Yixia Zhao, Lili Zhai, Ran Zhong, Changyin Li, Xiaoting Zou, Jiao Meng, Antony K Chen, Pier Lorenzo Puri, Meihong Chen, Dahai Zhu
Long non-coding RNAs (lncRNAs) are important regulators of diverse biological processes. Here we report on functional identification and characterization of a novel long intergenic non-coding RNA with MyoD-regulated and skeletal muscle-restricted expression that promotes the activation of the myogenic program, and is therefore termed Linc-RAM (Linc-RNA Activator of Myogenesis). Linc-RAM is transcribed from an intergenic region of myogenic cells and its expression is upregulated during myogenesis. Notably, in vivo functional studies show that Linc-RAM knockout mice display impaired muscle regeneration due to the differentiation defect of satellite cells...
January 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28060558/the-connection-between-brg1-ctcf-and-topoisomerases-at-tad-boundaries
#3
A Rasim Barutcu, Jane B Lian, Janet L Stein, Gary S Stein, Anthony N Imbalzano
The eukaryotic genome is partitioned into topologically associating domains (TADs). Despite recent advances characterizing TADs and TAD boundaries, the organization of these structures is an important dimension of genome architecture and function that is not well understood. Recently, we demonstrated that knockdown of BRG1, an ATPase driving the chromatin remodeling activity of mammalian SWI/SNF enzymes, globally alters long-range genomic interactions and results in a reduction of TAD boundary strength. We provided evidence suggesting that this effect may be due to BRG1 affecting nucleosome occupancy around CTCF sites present at TAD boundaries...
January 6, 2017: Nucleus
https://www.readbyqxmd.com/read/28053089/individual-bromodomains-of-polybromo-1-contribute-to-chromatin-association-and-tumor-suppression-in-clear-cell-renal-carcinoma
#4
Elizabeth G Porter, Emily C Dykhuizen
The architecture of chromatin is governed, in part, by adenosine triphosphate (ATP)-dependent chromatin remodelers. These multi-protein complexes contain targeting domains that recognize posttranslational marks on histones. One such targeting domain is the bromodomain (BD), which recognizes acetyl-lysines and recruits proteins to sites of acetylation across the genome. Polybromo1 (PBRM1), a subunit of the polybromo-associated BRG1- or hBRM-associated factors (P-BAF) chromatin remodeler, contains six tandem BDs and is frequently mutated in Renal Clear Cell Carcinoma (ccRCC)...
January 4, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28038711/smarca4-and-smarca2-deficiency-in-non-small-cell-lung-cancer-immunohistochemical-survey-of-316-consecutive-specimens
#5
Esther Herpel, Ralf J Rieker, Hendrik Dienemann, Thomas Muley, Michael Meister, Arndt Hartmann, Arne Warth, Abbas Agaimy
The chromatin remodeling switch sucrose nonfermentable (SWI/SNF) complex has been increasingly implicated in the pathogenesis and dedifferentiation of neoplasms from several organs with prognostic and potential therapeutic implications. We herein investigated the expression of the SWI/SNF complex catalytic subunits SMARCA4 (BRG1) and SMARCA2 (BRM) in 316 consecutive non-small cell lung cancer (NSCLC) specimens on tissue microarrays (171 adenocarcinomas [ADCAs], 130 squamous cell carcinomas [SCCs], 9 adenosquamous carcinomas, and 6 large cell carcinomas) excluding undifferentiated/giant cell or rhabdoid carcinomas...
February 2017: Annals of Diagnostic Pathology
https://www.readbyqxmd.com/read/28025236/otx2-defines-a-subgroup-of-atypical-teratoid-rhabdoid-tumors-with-close-relationship-to-choroid-plexus-tumors
#6
Anna Sophia Japp, Ludger Klein-Hitpass, Dorota Denkhaus, Torsten Pietsch
Atypical teratoid rhabdoid tumors (ATRT) are highly malignant brain tumors of early childhood that have been regarded as a homogenous entity characterized by inactivation of the SMARCB1/INI1 or SMARCA4/BRG1 genes as the only characteristic alteration. Recent studies suggest that similar to other embryonal tumors ATRT can also be divided into subgroups based on their mRNA or methylation profiles. Using microarray-based expression analysis of 12 patient ATRT specimens we demonstrated the existence of 2 subgroups of ATRT...
December 26, 2016: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28002318/brahma-related-gene-1-induces-apoptosis-in-a-p53-dependent-manner-in-human-rheumatoid-fibroblast-like-synoviocyte-mh7a
#7
Hongli Hou, Weipeng Xing, Wuyin Li
Blocked apoptosis and aggressive inflammatory responses occur in fibroblast-like synoviocyte (FLS) of rheumatoid arthritis (RA) patients. Although Brahma-related gene 1 (BRG1) is considered as a tumor suppressor, few research covers its role in RA. This study aims to reveal effects and potential mechanisms of BRG1 in human FLS cell line MH7A.BRG1 expression in MH7A cells was altered by transfection of overexpression vectors or short hairpin RNAs (shRNAs). Cell viability and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry after transfection...
December 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27941795/smarca4-atpase-mutations-disrupt-direct-eviction-of-prc1-from-chromatin
#8
Benjamin Z Stanton, Courtney Hodges, Joseph P Calarco, Simon M G Braun, Wai Lim Ku, Cigall Kadoch, Keji Zhao, Gerald R Crabtree
Trithorax-group proteins and their mammalian homologs, including those in BAF (mSWI/SNF) complexes, are known to oppose the activity of Polycomb repressive complexes (PRCs). This opposition underlies the tumor-suppressive role of BAF subunits and is expected to contribute to neurodevelopmental disorders. However, the mechanisms underlying opposition to Polycomb silencing are poorly understood. Here we report that recurrent disease-associated mutations in BAF subunits induce genome-wide increases in PRC deposition and activity...
December 12, 2016: Nature Genetics
https://www.readbyqxmd.com/read/27940962/rb-localizes-to-dna-double-strand-breaks-and-promotes-dna-end-resection-and-homologous-recombination-through-the-recruitment-of-brg1
#9
Renier Vélez-Cruz, Swarnalatha Manickavinayaham, Anup K Biswas, Regina Weaks Clary, Tolkappiyan Premkumar, Francesca Cole, David G Johnson
The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double-strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome instability...
November 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/27935965/bypass-of-candida-albicans-filamentation-biofilm-regulators-through-diminished-expression-of-protein-kinase-cak1
#10
Carol A Woolford, Katherine Lagree, Wenjie Xu, Tatyana Aleynikov, Hema Adhikari, Hiram Sanchez, Paul J Cullen, Frederick Lanni, David R Andes, Aaron P Mitchell
Biofilm formation on implanted medical devices is a major source of lethal invasive infection by Candida albicans. Filamentous growth of this fungus is tied to biofilm formation because many filamentation-associated genes are required for surface adherence. Cell cycle or cell growth defects can induce filamentation, but we have limited information about the coupling between filamentation and filamentation-associated gene expression after cell cycle/cell growth inhibition. Here we identified the CDK activating protein kinase Cak1 as a determinant of filamentation and filamentation-associated gene expression through a screen of mutations that diminish expression of protein kinase-related genes implicated in cell cycle/cell growth control...
December 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27929112/chromatin-remodelling-factor-brg1-regulates-myocardial-proliferation-and-regeneration-in-zebrafish
#11
Chenglu Xiao, Lu Gao, Yu Hou, Congfei Xu, Nannan Chang, Fang Wang, Keping Hu, Aibin He, Ying Luo, Jun Wang, Jinrong Peng, Fuchou Tang, Xiaojun Zhu, Jing-Wei Xiong
The zebrafish possesses a remarkable capacity of adult heart regeneration, but the underlying mechanisms are not well understood. Here we report that chromatin remodelling factor Brg1 is essential for adult heart regeneration. Brg1 mRNA and protein are induced during heart regeneration. Transgenic over-expression of dominant-negative Xenopus Brg1 inhibits the formation of BrdU(+)/Mef2C(+) and Tg(gata4:EGFP) cardiomyocytes, leading to severe cardiac fibrosis and compromised myocardial regeneration. RNA-seq and RNAscope analyses reveal that inhibition of Brg1 increases the expression of cyclin-dependent kinase inhibitors such as cdkn1a and cdkn1c in the myocardium after ventricular resection; and accordingly, myocardial-specific expression of dn-xBrg1 blunts myocardial proliferation and regeneration...
December 8, 2016: Nature Communications
https://www.readbyqxmd.com/read/27914010/recruitment-by-the-repressor-freud-1-of-histone-deacetylase-brg1-chromatin-remodeling-complexes-to-strengthen-htr1a-gene-repression
#12
Tatiana Souslova, Kim Mirédin, Anne M Millar, Paul R Albert
Five-prime repressor element under dual repression binding protein-1 (Freud-1)/CC2D1A is genetically linked to intellectual disability and implicated in neuronal development. Freud-1 represses the serotonin-1A (5-HT1A) receptor gene HTR1A by histone deacetylase (HDAC)-dependent or HDAC-independent mechanisms in 5-HT1A-negative (e.g., HEK-293) or 5-HT1A-expressing cells (SK-N-SH), respectively. To identify the underlying mechanisms, Freud-1-associated proteins were affinity-purified from HEK-293 nuclear extracts and members of the Brg1/SMARCCA chromatin remodeling and Sin3A-HDAC corepressor complexes were identified...
December 2, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27905400/lncbrm-initiates-yap1-signalling-activation-to-drive-self-renewal-of-liver-cancer-stem-cells
#13
Pingping Zhu, Yanying Wang, Jiayi Wu, Guanling Huang, Benyu Liu, Buqing Ye, Ying Du, Guangxia Gao, Yong Tian, Lei He, Zusen Fan
Liver cancer stem cells (CSCs) may contribute to the high rate of recurrence and heterogeneity of hepatocellular carcinoma (HCC). However, the biology of hepatic CSCs remains largely undefined. Through analysis of transcriptome microarray data, we identify a long noncoding RNA (lncRNA) called lncBRM, which is highly expressed in liver CSCs and HCC tumours. LncBRM is required for the self-renewal maintenance of liver CSCs and tumour initiation. In liver CSCs, lncBRM associates with BRM to initiate the BRG1/BRM switch and the BRG1-embedded BAF complex triggers activation of YAP1 signalling...
December 1, 2016: Nature Communications
https://www.readbyqxmd.com/read/27879032/altered-expression-of-brg1-and-histone-demethylases-and-aberrant-h3k4-methylation-in-less-developmentally-competent-embryos-at-the-time-of-embryonic-genome-activation
#14
Werner G Glanzner, Audrey Wachter, Ana Rita S Coutinho, Marcelo S Albornoz, Raj Duggavathi, Paulo B D GonÇAlves, Vilceu Bordignon
Epigenetics is a fundamental regulator underlying many biological functions, such as development and cell differentiation. Epigenetic modifications affect key chromatin regulation, including transcription and DNA repair, which are critical for normal embryo development. In this study, we profiled the expression of epigenetic modifiers and patterns of epigenetic changes in porcine embryos around the period of embryonic genome activation (EGA). We observed that Brahma-related gene 1 (BRG1) and Lysine demethylase 1A (KDM1A), which can alter the methylation status of lysine 4 in histone 3 (H3K4), localize to the nucleus at Day 3-4 of development...
November 23, 2016: Molecular Reproduction and Development
https://www.readbyqxmd.com/read/27852072/the-chromatin-remodeling-enzyme-brg1-promotes-colon-cancer-progression-via-positive-regulation-of-wnt3a
#15
Shengtao Lin, Tao Jiang, Ling Ye, Zhongbo Han, Yuan Liu, Chenchen Liu, Chenwei Yuan, Senlin Zhao, Jian Chen, Jingtao Wang, Huamei Tang, Su Lu, Liguang Yang, Xiaoliang Wang, Dongwang Yan, Zhihai Peng, Junwei Fan
In this study, we aimed to elucidate the clinical significance and underlying mechanisms of BRG1 in colon cancer. In the clinical analysis, overexpression of BRG1 correlates with colon cancer progression in two cohorts (n = 191 and n = 75). Kaplan-Meier survival analysis revealed that BRG1 is a prognosis predictor for overall survival (P < 0.001) and disease-free survival (P = 0.001). Knocking down BRG1 expression significantly suppressed the proliferation and invasion in colon cancer cells. The expression pattern of WNT3A is consistent with BRG1 in colon cancer tissues and WNT3A expression was inhibited in BRG1 knockdown cells...
November 12, 2016: Oncotarget
https://www.readbyqxmd.com/read/27797380/dna-demethylation-induces-sall4-gene-re-expression-in-subgroups-of-hepatocellular-carcinoma-associated-with-hepatitis-b-or-c-virus-infection
#16
H Fan, Z Cui, H Zhang, S K Mani, A Diab, L Lefrancois, N Fares, P Merle, O Andrisani
Sal-like protein 4 (SALL4), an embryonic stem cell transcriptional regulator, is re-expressed by an unknown mechanism in poor prognosis hepatocellular carcinoma (HCC), often associated with chronic hepatitis B virus (HBV) infection. Herein, we investigated the mechanism of SALL4 re-expression in HBV-related HCCs. We performed bisulfite sequencing PCR of genomic DNA isolated from HBV-related HCCs and HBV replicating cells, and examined DNA methylation of a CpG island located downstream from SALL4 transcriptional start site (TSS)...
October 31, 2016: Oncogene
https://www.readbyqxmd.com/read/27764136/immunohistochemistry-successfully-uncovers-intratumoral-heterogeneity-and-widespread-co-losses-of-chromatin-regulators-in-clear-cell-renal-cell-carcinoma
#17
Wei Jiang, Essel Dulaimi, Karthik Devarajan, Theodore Parsons, Qiong Wang, Lili Liao, Eun-Ah Cho, Raymond O'Neill, Charalambos Solomides, Stephen C Peiper, Joseph R Testa, Robert Uzzo, Haifeng Yang
Recent studies have shown that intratumoral heterogeneity (ITH) is prevalent in clear cell renal cell carcinoma (ccRCC), based on DNA sequencing and chromosome aberration analysis of multiple regions from the same tumor. VHL mutations were found to be universal throughout individual tumors when it occurred (ubiquitous), while the mutations in other tumor suppressor genes tended to be detected only in parts of the tumors (subclonal). ITH has been studied mostly by DNA sequencing in limited numbers of samples, either by whole genome sequencing or by targeted sequencing...
2016: PloS One
https://www.readbyqxmd.com/read/27736764/beauvericin-potentiates-azole-activity-via-inhibition-of-multidrug-efflux-blocks-candida-albicans-morphogenesis-and-is-effluxed-via-yor1-and-circuitry-controlled-by-zcf29
#18
Tanvi Shekhar-Guturja, Walters Aji Tebung, Harley Mount, Ningning Liu, Julia R Köhler, Malcolm Whiteway, Leah E Cowen
Invasive fungal infections are a leading cause of human mortality. Effective treatment is hindered by the rapid emergence of resistance to the limited number of antifungal drugs, demanding new strategies to treat life-threatening fungal infections. Here, we explore a powerful strategy to enhance antifungal efficacy against leading human fungal pathogens by using the natural product beauvericin. We found that beauvericin potentiates the activity of azole antifungals against azole-resistant Candida isolates via inhibition of multidrug efflux and that beauvericin itself is effluxed via Yor1...
December 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27700223/steroid-hormone-receptors-silence-genes-by-a-chromatin-targeted-mechanism-similar-to-those-used-for-gene-activation
#19
A Silvina Nacht, Miguel Beato, Guillermo P Vicent
How genes are repressed by steroid hormones remains a matter of debate and several indirect mechanisms have been proposed. We found that the ligand-activated progesterone receptor (PR) recruits to the promoter of down-regulated genes a repressor complex composed of HP1γ, the lysine demethylase LSD1, histone deacetylases, coREST, the RNA SRA and the ATPase BRG1. BRG1 is needed for chromatin remodeling and facilitates the deposition of linker histone variant H1.2, which compacts chromatin and hinders RNA polymerase loading and transcription...
October 4, 2016: Transcription
https://www.readbyqxmd.com/read/27697157/chromatin-remodeling-in-addiction-brg1-smad3-interaction-contributes-to-cued-reinstatement-of-cocaine-seeking
#20
Alexander C W Smith
No abstract text is available yet for this article.
November 1, 2016: Biological Psychiatry
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