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https://www.readbyqxmd.com/read/29153843/aberrant-activation-of-a-gastrointestinal-transcriptional-circuit-in-prostate-cancer-mediates-castration-resistance
#1
Shipra Shukla, Joanna Cyrta, Devan A Murphy, Edward G Walczak, Leili Ran, Praveen Agrawal, Yuanyuan Xie, Yuedan Chen, Shangqian Wang, Yu Zhan, Dan Li, Elissa W P Wong, Andrea Sboner, Himisha Beltran, Juan Miguel Mosquera, Jessica Sher, Zhen Cao, John Wongvipat, Richard P Koche, Anuradha Gopalan, Deyou Zheng, Mark A Rubin, Howard I Scher, Ping Chi, Yu Chen
Prostate cancer exhibits a lineage-specific dependence on androgen signaling. Castration resistance involves reactivation of androgen signaling or activation of alternative lineage programs to bypass androgen requirement. We describe an aberrant gastrointestinal-lineage transcriptome expressed in ∼5% of primary prostate cancer that is characterized by abbreviated response to androgen-deprivation therapy and in ∼30% of castration-resistant prostate cancer. This program is governed by a transcriptional circuit consisting of HNF4G and HNF1A...
November 3, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29100329/cancer-cell-line-specific-co-factors-modulate-the-foxm1-cistrome
#2
Yue Wang, Matthew H Ung, Tian Xia, Wenqing Cheng, Chao Cheng
ChIP-seq has been commonly applied to identify genomic occupation of transcription factors (TFs) in a context-specific manner. It is generally assumed that a TF should have similar binding patterns in cells from the same or closely related tissues. Surprisingly, this assumption has not been carefully examined. To this end, we systematically compared the genomic binding of the cell cycle regulator FOXM1 in eight cell lines from seven different human tissues at binding signal, peaks and target genes levels. We found that FOXM1 binding in ER-positive breast cancer cell line MCF-7 are distinct comparing to those in not only other non-breast cell lines, but also MDA-MB-231, ER-negative breast cancer cell line...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29092952/timer-a-web-server-for-comprehensive-analysis-of-tumor-infiltrating-immune-cells
#3
Taiwen Li, Jingyu Fan, Binbin Wang, Nicole Traugh, Qianming Chen, Jun S Liu, Bo Li, X Shirley Liu
Recent clinical successes of cancer immunotherapy necessitate the investigation of the interaction between malignant cells and the host immune system. However, elucidation of complex tumor-immune interactions presents major computational and experimental challenges. Here, we present Tumor Immune Estimation Resource (TIMER; cistrome.shinyapps.io/timer) to comprehensively investigate molecular characterization of tumor-immune interactions. Levels of six tumor-infiltrating immune subsets are precalculated for 10,897 tumors from 32 cancer types...
November 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/29092931/cistrome-cancer-a-web-resource-for-integrative-gene-regulation-modeling-in-cancer
#4
Shenglin Mei, Clifford A Meyer, Rongbin Zheng, Qian Qin, Qiu Wu, Peng Jiang, Bo Li, Xiaohui Shi, Binbin Wang, Jingyu Fan, Celina Shih, Myles Brown, Chongzhi Zang, X Shirley Liu
Cancer results from a breakdown of normal gene expression control, so the study of gene regulation is critical to cancer research. To gain insight into the transcriptional and epigenetic factors regulating abnormal gene expression patterns in cancers, we developed the Cistrome Cancer web resource (http://cistrome.org/CistromeCancer/). We conducted the systematic integration and modeling of over 10,000 tumor molecular profiles from The Cancer Genome Atlas (TCGA) with over 23,000 ChIP-seq and chromatin accessibility profiles from our Cistrome collection...
November 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/29059155/reactivation-of-androgen-receptor-regulated-lipid-biosynthesis-drives-the-progression-of-castration-resistant-prostate-cancer
#5
W Han, S Gao, D Barrett, M Ahmed, D Han, J A Macoska, H H He, C Cai
Androgen receptor (AR) is a transcriptional activator that, in prostate cells, stimulates gene expression required for various cellular functions, including metabolisms and proliferation. AR signaling is also essential for the development of hormone-dependent prostate cancer (PCa) and its activity can be blocked by androgen-deprivation therapies (ADTs). Although PCa patients initially respond well to ADTs, the cancer inevitably relapses and progresses to lethal castration-resistant prostate cancer (CRPC). Although AR activity is generally restored in CRPC despite the castrate level of androgens, it is unclear whether AR signaling is significantly reprogrammed...
October 23, 2017: Oncogene
https://www.readbyqxmd.com/read/29027168/chip-re-chip-co-occupancy-analysis-by-sequential-chromatin-immunoprecipitation
#6
Timothy V Beischlag, Gratien G Prefontaine, Oliver Hankinson
Chromatin immunoprecipitation (ChIP) exploits the specific interactions between DNA and DNA-associated proteins. It can be used to examine a wide range of experimental parameters. A number of proteins bound at the same genomic location can identify a multi-protein chromatin complex where several proteins work together to regulate gene transcription or chromatin configuration. In many instances, this can be achieved using sequential ChIP; or simply, ChIP-re-ChIP. Whether it is for the examination of specific transcriptional or epigenetic regulators, or for the identification of cistromes, the ability to perform a sequential ChIP adds a higher level of power and definition to these analyses...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28925401/endogenous-androgen-receptor-proteomic-profiling-reveals-genomic-subcomplex-involved-in-prostate-tumorigenesis
#7
S Stelloo, E Nevedomskaya, Y Kim, L Hoekman, O B Bleijerveld, T Mirza, L F A Wessels, W M van Weerden, A F M Altelaar, A M Bergman, W Zwart
Androgen receptor (AR) is a key player in prostate cancer development and progression. Here we applied immunoprecipitation mass spectrometry of endogenous AR in LNCaP cells to identify components of the AR transcriptional complex. In total, 66 known and novel AR interactors were identified in the presence of synthetic androgen, most of which were critical for AR-driven prostate cancer cell proliferation. A subset of AR interactors required for LNCaP proliferation were profiled using chromatin immunoprecipitation assays followed by sequencing, identifying distinct genomic subcomplexes of AR interaction partners...
September 18, 2017: Oncogene
https://www.readbyqxmd.com/read/28887309/phosphorylation-of-the-oncogenic-transcription-factor-erg-in-prostate-cells-dissociates-polycomb-repressive-complex-2-allowing-target-gene-activation
#8
Vivekananda Kedage, Brady G Strittmatter, Paige B Dausinas, Peter C Hollenhorst
In ∼50% of prostate cancers, chromosomal rearrangements cause the fusion of the promoter and 5'-UTR of the androgen-regulated TMPRSS2 (transmembrane protease, serine 2) gene to the open reading frame of ERG, encoding an ETS family transcription factor. This fusion results in expression of full-length or N-terminally truncated ERG protein in prostate epithelia. ERG is not expressed in normal prostate epithelia, but when expressed, it promotes tumorigenesis via altered gene expression, stimulating epithelial-mesenchymal transition, cellular migration/invasion, and transformation...
October 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28873439/crispr-focus-a-web-server-for-designing-focused-crispr-screening-experiments
#9
Qingyi Cao, Jian Ma, Chen-Hao Chen, Han Xu, Zhi Chen, Wei Li, X Shirley Liu
The recently developed CRISPR screen technology, based on the CRISPR/Cas9 genome editing system, enables genome-wide interrogation of gene functions in an efficient and cost-effective manner. Although many computational algorithms and web servers have been developed to design single-guide RNAs (sgRNAs) with high specificity and efficiency, algorithms specifically designed for conducting CRISPR screens are still lacking. Here we present CRISPR-FOCUS, a web-based platform to search and prioritize sgRNAs for CRISPR screen experiments...
2017: PloS One
https://www.readbyqxmd.com/read/28870774/ets-transcription-factor-family-member-gabpa-contributes-to-vitamin-d-receptor-target-gene-regulation
#10
Sabine Seuter, Antonio Neme, Carsten Carlberg
Binding motifs of the ETS-domain transcription factor GABPA are found with high significance below the summits of the vitamin D receptor (VDR) cistrome. VDR is the nuclear receptor for the biologically most active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). In this study, we determined the GABPA cistrome in THP-1 human monocytes and found that it is comprised of 3822 genomic loci, some 20% of which were modulated by 1,25(OH)2D3. The GABPA cistrome showed a high overlap rate with accessible chromatin and the pioneer transcription factor PU...
September 11, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28863148/a-conceptual-and-computational-framework-for-modelling-and-understanding-the-non-equilibrium-gene-regulatory-networks-of-mouse-embryonic-stem-cells
#11
Richard B Greaves, Sabine Dietmann, Austin Smith, Susan Stepney, Julianne D Halley
The capacity of pluripotent embryonic stem cells to differentiate into any cell type in the body makes them invaluable in the field of regenerative medicine. However, because of the complexity of both the core pluripotency network and the process of cell fate computation it is not yet possible to control the fate of stem cells. We present a theoretical model of stem cell fate computation that is based on Halley and Winkler's Branching Process Theory (BPT) and on Greaves et al.'s agent-based computer simulation derived from that theoretical model...
September 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28820292/p53-binding-sites-in-normal-and-cancer-cells-are-characterized-by-distinct-chromatin-context
#12
Feifei Bao, Peter R LoVerso, Jeffrey N Fisk, Victor B Zhurkin, Feng Cui
The tumor suppressor protein p53 interacts with DNA in a sequence-dependent manner. Thousands of p53 binding sites have been mapped genome-wide in normal and cancer cells. However, the way p53 selectively binds its cognate sites in different types of cells is not fully understood. Here, we performed a comprehensive analysis of 25 published p53 cistromes and identified 3,551 and 6,039 'high-confidence' binding sites in normal and cancer cells, respectively. Our analysis revealed two distinct epigenetic features underlying p53-DNA interactions in vivo...
August 18, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28819152/dissecting-the-genomic-activity-of-a-transcriptional-regulator-by-the-integrative-analysis-of-omics-data
#13
Giulio Ferrero, Valentina Miano, Marco Beccuti, Gianfranco Balbo, Michele De Bortoli, Francesca Cordero
In the study of genomic regulation, strategies to integrate the data produced by Next Generation Sequencing (NGS)-based technologies in a meaningful ensemble are eagerly awaited and must continuously evolve. Here, we describe an integrative strategy for the analysis of data generated by chromatin immunoprecipitation followed by NGS which combines algorithms for data overlap, normalization and epigenetic state analysis. The performance of our strategy is illustrated by presenting the analysis of data relative to the transcriptional regulator Estrogen Receptor alpha (ERα) in MCF-7 breast cancer cells and of Glucocorticoid Receptor (GR) in A549 lung cancer cells...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28805822/intrinsic-bet-inhibitor-resistance-in-spop-mutated-prostate-cancer-is-mediated-by-bet-protein-stabilization-and-akt-mtorc1-activation
#14
Pingzhao Zhang, Dejie Wang, Yu Zhao, Shancheng Ren, Kun Gao, Zhenqing Ye, Shangqian Wang, Chun-Wu Pan, Yasheng Zhu, Yuqian Yan, Yinhui Yang, Di Wu, Yundong He, Jun Zhang, Daru Lu, Xiuping Liu, Long Yu, Shimin Zhao, Yao Li, Dong Lin, Yuzhuo Wang, Liguo Wang, Yu Chen, Yinghao Sun, Chenji Wang, Haojie Huang
Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising anticancer therapies. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) is the most frequently mutated in primary prostate cancer. Here we demonstrate that wild-type SPOP binds to and induces ubiquitination and proteasomal degradation of BET proteins (BRD2, BRD3 and BRD4) by recognizing a degron motif common among them. In contrast, prostate cancer-associated SPOP mutants show impaired binding to BET proteins, resulting in decreased proteasomal degradation and accumulation of these proteins in prostate cancer cell lines and patient specimens and causing resistance to BET inhibitors...
September 2017: Nature Medicine
https://www.readbyqxmd.com/read/28774779/extensive-and-functional-overlap-of-the-stat6-and-rxr-cistromes-in-the-active-enhancer-repertoire-of-human-cd14-monocyte-derived-differentiating-macrophages
#15
Zsolt Czimmerer, Zsuzsanna S Nagy, Gergely Nagy, Attila Horvath, Timea Silye-Cseh, Agnes Kriston, David Jonas, Sascha Sauer, Laszlo Steiner, Bence Daniel, Jean-Francois Deleuze, Laszlo Nagy
Macrophages are able to differentiate into classically polarized (M1) or alternatively polarized (M2) states upon encountering pro-inflammatory cytokines such as interferon (IFN) γ or anti-inflammatory cytokines such as interleukin (IL) -4/IL-13, respectively. Moreover, macrophages are known to regulate lipid metabolism via multiple members of the nuclear hormone receptor family, including the retinoid X receptors (RXR). It has been also documented that cytokines are able to modulate macrophage responses to lipid signals but the nature of these interactions and the underlying mechanisms of these processes especially at the level of the chromatinized genome are not well understood...
July 31, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28751734/glucocorticoid-therapy-regulates-podocyte-motility-by-inhibition-of-rac1
#16
James C McCaffrey, Nicholas J Webb, Toryn M Poolman, Maryline Fresquet, Cressida Moxey, Leo A H Zeef, Ian J Donaldson, David W Ray, Rachel Lennon
Nephrotic syndrome (NS) occurs when the glomerular filtration barrier becomes excessively permeable leading to massive proteinuria. In childhood NS, immune system dysregulation has been implicated and increasing evidence points to the central role of podocytes in the pathogenesis. Children with NS are typically treated with an empiric course of glucocorticoid (Gc) therapy; a class of steroids that are activating ligands for the glucocorticoid receptor (GR) transcription factor. Although Gc-therapy has been the cornerstone of NS management for decades, the mechanism of action, and target cell, remain poorly understood...
July 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28729413/breast-cancer-suppression-by-progesterone-receptors-is-mediated-by-their-modulation-of-estrogen-receptors-and-rna-polymerase-iii
#17
Jessica Finlay-Schultz, Austin E Gillen, Heather M Brechbuhl, Joshua J Ivie, Shawna B Matthews, Britta M Jacobsen, David L Bentley, Peter Kabos, Carol A Sartorius
Greater than 50% of estrogen receptor (ER)-positive breast cancers coexpress the progesterone receptor (PR), which can directly and globally modify ER action to attenuate tumor growth. However, whether this attenuation is mediated only through PR-ER interaction remains unknown. To address this question, we assessed tumor growth in ER/PR-positive patient-derived xenograft models of breast cancer, where both natural and synthetic progestins were found to antagonize the mitogenic effects of estrogens. Probing the genome-wide mechanisms by which this occurs, we documented that chronic progestin treatment blunted ER-mediated gene expression up to 2-fold at the level of mRNA transcripts...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28726847/mapping-genome-wide-transcription-factor-binding-sites-using-dap-seq
#18
Anna Bartlett, Ronan C O'Malley, Shao-Shan Carol Huang, Mary Galli, Joseph R Nery, Andrea Gallavotti, Joseph R Ecker
To enable low-cost, high-throughput generation of cistrome and epicistrome maps for any organism, we developed DNA affinity purification sequencing (DAP-seq), a transcription factor (TF)-binding site (TFBS) discovery assay that couples affinity-purified TFs with next-generation sequencing of a genomic DNA library. The method is fast, inexpensive, and more easily scaled than chromatin immunoprecipitation sequencing (ChIP-seq). DNA libraries are constructed using native genomic DNA from any source of interest, preserving cell- and tissue-specific chemical modifications that are known to affect TF binding (such as DNA methylation) and providing increased specificity as compared with in silico predictions based on motifs from methods such as protein-binding microarrays (PBMs) and systematic evolution of ligands by exponential enrichment (SELEX)...
August 2017: Nature Protocols
https://www.readbyqxmd.com/read/28712921/selective-regulation-of-biological-processes-by-vitamin-d-based-on-the-spatio-temporal-cistrome-of-its-receptor
#19
Antonio Neme, Sabine Seuter, Carsten Carlberg
The transcription factor vitamin D receptor (VDR) is the exclusive nuclear target of the biologically active form of vitamin D (1,25(OH)2D3). In THP-1 human monocytes we obtained a highly accurate VDR cistrome after 2 and 24h ligand stimulation comprising >11,600 genomic loci, 78% of which were detected exclusively after 24h. In contrast, a group of 510 persistent VDR sites occurred at all conditions and some 2100 VDR loci were only transiently occupied. Machine learning and statistical analysis as well as a comparison with the re-analyzed B cell VDR cistrome indicated a subgroup of 339 highly conserved persistent VDR sites that were suited best for describing vitamin D-triggered gene regulatory scenarios...
September 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28702326/rev-erb-co-regulates-muscle-regeneration-via-tethered-interaction-with-the-nf-y-cistrome
#20
Ryan D Welch, Chun Guo, Monideepa Sengupta, Katherine J Carpenter, Natalie A Stephens, Stacy A Arnett, Marvin J Meyers, Lauren M Sparks, Steven R Smith, Jinsong Zhang, Thomas P Burris, Colin A Flaveny
OBJECTIVE: The loss of skeletal muscle mass and strength are a central feature of traumatic injury and degenerative myopathies. Unfortunately, pharmacological interventions typically fail to stem the long-term decline in quality of life. Reduced Rev-Erb-mediated gene suppression in cultured C2C12 myoblasts has been shown to stimulate myoblast differentiation. Yet the mechanisms that allow Rev-Erb to pleiotropically inhibit muscle differentiation are not well understood. In this study, we sought to elucidate the role of Rev-Erb in the regulation of muscle differentiation and regeneration in vivo...
July 2017: Molecular Metabolism
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