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https://www.readbyqxmd.com/read/28628103/a-common-haplotype-lowers-pu-1-expression-in-myeloid-cells-and-delays-onset-of-alzheimer-s-disease
#1
Kuan-Lin Huang, Edoardo Marcora, Anna A Pimenova, Antonio F Di Narzo, Manav Kapoor, Sheng Chih Jin, Oscar Harari, Sarah Bertelsen, Benjamin P Fairfax, Jake Czajkowski, Vincent Chouraki, Benjamin Grenier-Boley, Céline Bellenguez, Yuetiva Deming, Andrew McKenzie, Towfique Raj, Alan E Renton, John Budde, Albert Smith, Annette Fitzpatrick, Joshua C Bis, Anita DeStefano, Hieab H H Adams, M Arfan Ikram, Sven van der Lee, Jorge L Del-Aguila, Maria Victoria Fernandez, Laura Ibañez, Rebecca Sims, Valentina Escott-Price, Richard Mayeux, Jonathan L Haines, Lindsay A Farrer, Margaret A Pericak-Vance, Jean Charles Lambert, Cornelia van Duijn, Lenore Launer, Sudha Seshadri, Julie Williams, Philippe Amouyel, Gerard D Schellenberg, Bin Zhang, Ingrid Borecki, John S K Kauwe, Carlos Cruchaga, Ke Hao, Alison M Goate
A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU...
June 19, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28507152/embryonic-transcription-factor-sox9-drives-breast-cancer-endocrine-resistance
#2
Rinath Jeselsohn, MacIntosh Cornwell, Matthew Pun, Gilles Buchwalter, Mai Nguyen, Clyde Bango, Ying Huang, Yanan Kuang, Cloud Paweletz, Xiaoyong Fu, Agostina Nardone, Carmine De Angelis, Simone Detre, Andrew Dodson, Hisham Mohammed, Jason S Carroll, Michaela Bowden, Prakash Rao, Henry W Long, Fugen Li, Mitchell Dowsett, Rachel Schiff, Myles Brown
The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases...
May 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28483704/genome-wide-analysis-of-ar-binding-and-comparison-with-transcript-expression-in-primary-human-fetal-prostate-fibroblasts-and-cancer-associated-fibroblasts
#3
REVIEW
Claire Nash, Nadia Boufaied, Ian G Mills, Omar E Franco, Simon W Hayward, Axel A Thomson
The androgen receptor (AR) is a transcription factor, and key regulator of prostate development and cancer, which has discrete functions in stromal versus epithelial cells. AR expressed in mesenchyme is necessary and sufficient for prostate development while loss of stromal AR is predictive of prostate cancer progression. Many studies have characterized genome-wide binding of AR in prostate tumour cells but none have used primary mesenchyme or stroma. We applied ChIPseq to identify genomic AR binding sites in primary human fetal prostate fibroblasts and patient derived cancer associated fibroblasts, as well as the WPMY1 cell line overexpressing AR...
May 5, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28407733/the-kr%C3%A3-ppel-like-factor-9-cistrome-in-mouse-hippocampal-neurons-reveals-predominant-transcriptional-repression-via-proximal-promoter-binding
#4
Joseph R Knoedler, Arasakumar Subramani, Robert J Denver
BACKGROUND: Krüppel-like factor 9 (Klf9) is a zinc finger transcription factor that functions in neural cell differentiation, but little is known about its genomic targets or mechanism of action in neurons. RESULTS: We used the mouse hippocampus-derived neuronal cell line HT22 to identify genes regulated by Klf9, and we validated our findings in mouse hippocampus. We engineered HT22 cells to express a Klf9 transgene under control of the tetracycline repressor, and used RNA sequencing to identify genes modulated by Klf9...
April 13, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28400425/the-logic-of-transcriptional-regulator-recruitment-architecture-at-cis-regulatory-modules-controlling-liver-functions
#5
Julie Dubois-Chevalier, Vanessa Dubois, Hélène Dehondt, Parisa Mazrooei, Claire Mazuy, Aurélien A Sérandour, Céline Gheeraert, Penderia Guillaume, Eric Baugé, Bruno Derudas, Nathalie Hennuyer, Réjane Paumelle, Guillemette Marot, Jason S Carroll, Mathieu Lupien, Bart Staels, Philippe Lefebvre, Jérôme Eeckhoute
Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis-regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic, and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs...
June 2017: Genome Research
https://www.readbyqxmd.com/read/28306507/structural-and-molecular-mechanisms-of-cytokine-mediated-endocrine-resistance-in-human-breast-cancer-cells
#6
Joshua D Stender, Jerome C Nwachukwu, Irida Kastrati, Yohan Kim, Tobias Strid, Maayan Yakir, Sathish Srinivasan, Jason Nowak, Tina Izard, Erumbi S Rangarajan, Kathryn E Carlson, John A Katzenellenbogen, Xin-Qiu Yao, Barry J Grant, Hon S Leong, Chin-Yo Lin, Jonna Frasor, Kendall W Nettles, Christopher K Glass
Human breast cancers that exhibit high proportions of immune cells and elevated levels of pro-inflammatory cytokines predict poor prognosis. Here, we demonstrate that treatment of human MCF-7 breast cancer cells with pro-inflammatory cytokines results in ERα-dependent activation of gene expression and proliferation, in the absence of ligand or presence of 4OH-tamoxifen (TOT). Cytokine activation of ERα and endocrine resistance is dependent on phosphorylation of ERα at S305 in the hinge domain. Phosphorylation of S305 by IKKβ establishes an ERα cistrome that substantially overlaps with the estradiol (E2)-dependent ERα cistrome...
March 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28302717/regulatory-signatures-of-liver-regeneration-distilled-by-integrative-analysis-of-mrna-histone-methylation-and-proteomics
#7
Yoshihiro Sato, Yasutake Katoh, Mitsuyo Matsumoto, Masaki Sato, Masayuki Ebina, Ari Itoh-Nakadai, Ryo Funayama, Keiko Nakayama, Michiaki Unno, Kazuhiko Igarashi
The capacity of the liver to regenerate is likely to be encoded as a plasticity of molecular networks within the liver. By applying a combination of comprehensive analyses of the epigenome, transcriptome, and proteome, we herein depict the molecular landscape of liver regeneration. We demonstrated that histone H3 Lys-4 was trimethylated at the promoter regions of many loci, among which only a fraction, including cell-cycle-related genes, were transcriptionally up-regulated. A cistrome analysis guided by the histone methylation patterns and the transcriptome identified FOXM1 as the key transcription factor promoting liver regeneration, which was confirmed in vitro using a hepatocarcinoma cell line...
May 12, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28123935/deletion-of-histone-deacetylase-3-in-adult-beta-cells-improves-glucose-tolerance-via-increased-insulin-secretion
#8
Jarrett R Remsberg, Benjamin N Ediger, Wesley Y Ho, Manashree Damle, Zhenghui Li, Christopher Teng, Cristina Lanzillotta, Doris A Stoffers, Mitchell A Lazar
OBJECTIVE: Histone deacetylases are epigenetic regulators known to control gene transcription in various tissues. A member of this family, histone deacetylase 3 (HDAC3), has been shown to regulate metabolic genes. Cell culture studies with HDAC-specific inhibitors and siRNA suggest that HDAC3 plays a role in pancreatic β-cell function, but a recent genetic study in mice has been contradictory. Here we address the functional role of HDAC3 in β-cells of adult mice. METHODS: An HDAC3 β-cell specific knockout was generated in adult MIP-CreERT transgenic mice using the Cre-loxP system...
January 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28119415/interaction-with-zmynd11-mediates-opposing-roles-of-ras-responsive-transcription-factors-ets1-and-ets2
#9
Joshua P Plotnik, Peter C Hollenhorst
Aberrant activation of RAS/MAPK signaling is a driver of over one third of all human carcinomas. The homologous transcription factors ETS1 and ETS2 mediate activation of gene expression programs downstream of RAS/MAPK signaling. ETS1 is important for oncogenesis in many tumor types. However, ETS2 can act as an oncogene in some cellular backgrounds, and as a tumor suppressor in others, and the molecular mechanism responsible for this cell-type specific function remains unknown. Here, we show that ETS1 and ETS2 can regulate a cell migration gene expression program in opposite directions, and provide the first comparison of the ETS1 and ETS2 cistromes...
May 5, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28076760/enriching-the-circadian-proteome
#10
Joseph S Takahashi
Circadian clocks regulate most aspects of physiology and metabolism. Genome-wide approaches have uncovered widespread circadian rhythms in the transcriptome, cistrome, and epigenome of mice, and now two proteomics studies in this issue (Robles et al., 2016; Wang et al., 2016) reveal extensive circadian regulation of the nuclear and phosphoproteome.
January 10, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28055971/src-promotes-castration-recurrent-prostate-cancer-through-androgen-receptor-dependent-canonical-and-non-canonical-transcriptional-signatures
#11
Indranil Chattopadhyay, Jianmin Wang, Maochun Qin, Lingqiu Gao, Renae Holtz, Robert L Vessella, Robert W Leach, Irwin H Gelman
Progression of prostate cancer (PC) to castration-recurrent growth (CRPC) remains dependent on sustained expression and transcriptional activity of the androgen receptor (AR). A major mechanism contributing to CRPC progression is through the direct phosphorylation and activation of AR by Src-family (SFK) and ACK1 tyrosine kinases. However, the AR-dependent transcriptional networks activated by Src during CRPC progression have not been elucidated. Here, we show that activated Src (Src527F) induces androgen-independent growth in human LNCaP cells, concomitant with its ability to induce proliferation/survival genes normally induced by dihydrotestosterone (DHT) in androgen-dependent LNCaP and VCaP cells...
February 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28031249/transcription-factor-assisted-loading-and-enhancer-dynamics-dictate-the-hepatic-fasting-response
#12
Ido Goldstein, Songjoon Baek, Diego M Presman, Ville Paakinaho, Erin E Swinstead, Gordon L Hager
Fasting elicits transcriptional programs in hepatocytes leading to glucose and ketone production. This transcriptional program is regulated by many transcription factors (TFs). To understand how this complex network regulates the metabolic response to fasting, we aimed at isolating the enhancers and TFs dictating it. Measuring chromatin accessibility revealed that fasting massively reorganizes liver chromatin, exposing numerous fasting-induced enhancers. By utilizing computational methods in combination with dissecting enhancer features and TF cistromes, we implicated four key TFs regulating the fasting response: glucocorticoid receptor (GR), cAMP responsive element binding protein 1 (CREB1), peroxisome proliferator activated receptor alpha (PPARA), and CCAAT/enhancer binding protein beta (CEBPB)...
March 2017: Genome Research
https://www.readbyqxmd.com/read/28027912/integrative-genomic-approaches-to-dissect-clinically-significant-relationships-between-the-vdr-cistrome-and-gene-expression-in-primary-colon-cancer
#13
REVIEW
Mark D Long, Moray J Campbell
Recently, we undertook a pan-cancer analyses of the nuclear hormone receptor (NR) superfamily in The Cancer Genome Atlas (TCGA), and revealed that the vitamin D receptor (NR1I1/VDR) was commonly and significantly down-regulated specifically in colon adenocarcinoma cohort (COAD). To examine the consequence of down-regulated VDR expression we re-analyzed VDR chromatin immunoprecipitation sequencing (ChIP-Seq) data from LS180 colon cancer cells (GSE31939). This analysis identified 1809 loci that displayed significant (p...
December 24, 2016: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/27968908/epb41-a-novel-hepatoma-susceptibility-gene-dysregulated-by-c-myc-an-integrative-functional-genomics-study
#14
Xinyu Yang, Dianke Yu, Yanli Ren, Jinyu Wei, Wenting Pan, Changchun Zhou, Liqing Zhou, Yu Liu, Ming Yang
BACKGROUND: Genome-wide association studies (GWAS) have provided insight into cancer genetics. However, molecular mechanisms whereby many susceptibility single nucleotide polymorphisms (SNPs) identified by GWAS promote cancer heritability and risk are unknown. New research strategies to evaluate functionality are needed to systematically study causal genetic variants. METHODS: In this study, we developed an integrative functional genomics method to identify cancer susceptibility SNPs in transcription factor binding sites across the whole genome...
October 2016: Lancet
https://www.readbyqxmd.com/read/27964748/non-coding-single-nucleotide-variants-affecting-estrogen-receptor-binding-and-activity
#15
Amir Bahreini, Kevin Levine, Lucas Santana-Santos, Panayiotis V Benos, Peilu Wang, Courtney Andersen, Steffi Oesterreich, Adrian V Lee
BACKGROUND: Estrogen receptor (ER) activity is critical for the development and progression of the majority of breast cancers. It is known that ER is differentially bound to DNA leading to transcriptomic and phenotypic changes in different breast cancer models. We investigated whether single nucleotide variants (SNVs) in ER binding sites (regSNVs) contribute to ER action through changes in the ER cistrome, thereby affecting disease progression. Here we developed a computational pipeline to identify SNVs in ER binding sites using chromatin immunoprecipitation sequencing (ChIP-seq) data from ER+ breast cancer models...
December 13, 2016: Genome Medicine
https://www.readbyqxmd.com/read/27900343/divergence-and-rewiring-of-regulatory-networks-for-neural-development-between-human-and-other-species
#16
COMMENT
Ping Wang, Dejian Zhao, Shira Rockowitz, Deyou Zheng
Neural and brain development in human and other mammalian species are largely similar, but distinct features exist at the levels of macrostructure and underlying genetic control. Comparative studies of epigenetic regulation and transcription factor (TF) binding in humans, chimpanzees, rodents, and other species have found large differences in gene regulatory networks. A recent analysis of the cistromes of REST/NRSF, a critical transcriptional regulator for the nervous system, demonstrated that REST binding to syntenic genomic regions (i...
2016: Neurogenesis (Austin, Tex.)
https://www.readbyqxmd.com/read/27848897/bioinformatics-and-drug-discovery
#17
Xuhua Xia
Bioinformatic analysis can not only accelerate drug target identification and drug candidate screening and refinement, but also facilitate characterization of side effects and predict drug resistance. High-throughput data such as genomic, epigenetic, genome architecture, cistromic, transcriptomic, proteomic, and ribosome profiling data have all made significant contribution to mechanismbased drug discovery and drug repurposing. Accumulation of protein and RNA structures, as well as development of homology modeling and protein structure simulation, coupled with large structure databases of small molecules and metabolites, paved the way for more realistic protein-ligand docking experiments and more informative virtual screening...
2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/27802171/cooperative-binding-of-ap-1-and-tead4-modulates-the-balance-between-vascular-smooth-muscle-and-hemogenic-cell-fate
#18
Nadine Obier, Pierre Cauchy, Salam A Assi, Jane Gilmour, Michael Lie-A-Ling, Monika Lichtinger, Maarten Hoogenkamp, Laura Noailles, Peter N Cockerill, Georges Lacaud, Valerie Kouskoff, Constanze Bonifer
The transmission of extracellular signals into the nucleus involves inducible transcription factors, but how different signalling pathways act in a cell type-specific fashion is poorly understood. Here, we studied the regulatory role of the AP-1 transcription factor family in blood development using embryonic stem cell differentiation coupled with genome-wide transcription factor binding and gene expression analyses. AP-1 factors respond to MAP kinase signalling and comprise dimers of FOS, ATF and JUN proteins...
December 1, 2016: Development
https://www.readbyqxmd.com/read/27789702/cistrome-data-browser-a-data-portal-for-chip-seq-and-chromatin-accessibility-data-in-human-and-mouse
#19
Shenglin Mei, Qian Qin, Qiu Wu, Hanfei Sun, Rongbin Zheng, Chongzhi Zang, Muyuan Zhu, Jiaxin Wu, Xiaohui Shi, Len Taing, Tao Liu, Myles Brown, Clifford A Meyer, X Shirley Liu
Chromatin immunoprecipitation, DNase I hypersensitivity and transposase-accessibility assays combined with high-throughput sequencing enable the genome-wide study of chromatin dynamics, transcription factor binding and gene regulation. Although rapidly accumulating publicly available ChIP-seq, DNase-seq and ATAC-seq data are a valuable resource for the systematic investigation of gene regulation processes, a lack of standardized curation, quality control and analysis procedures have hindered extensive reuse of these data...
January 4, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27672034/crosstalk-between-androgen-and-pro-inflammatory-signaling-remodels-androgen-receptor-and-nf-%C3%AE%C2%BAb-cistrome-to-reprogram-the-prostate-cancer-cell-transcriptome
#20
Marjo Malinen, Einari A Niskanen, Minna U Kaikkonen, Jorma J Palvimo
Inflammatory processes and androgen signaling are critical for the growth of prostate cancer (PC), the most common cancer among males in Western countries. To understand the importance of potential interplay between pro-inflammatory and androgen signaling for gene regulation, we have interrogated the crosstalk between androgen receptor (AR) and NF-κB, a key transcriptional mediator of inflammatory responses, by utilizing genome-wide chromatin immunoprecipitation sequencing and global run-on sequencing in PC cells...
January 25, 2017: Nucleic Acids Research
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