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Ralph Stadhouders, Bobby W S Li, Marjolein J W de Bruijn, Antonio Gomez, Tata Nageswara Rao, Hans Jörg Fehling, Wilfred F J van IJcken, Ai Ing Lim, James P Di Santo, Thomas Graf, Rudi W Hendriks
BACKGROUND: Group 2 innate lymphoid cells (ILC2s) are major producers of cytokines driving allergic asthma and elevated numbers of ILC2s have been detected in blood and sputum of asthma patients. Asthma susceptibility has a strong genetic component, but the underlying mechanisms and whether asthma genetics impact ILC2 biology remains unclear. OBJECTIVE: To study the ILC2 transcriptome and epigenome during airway inflammation (AI) in order to couple these to genes and genetic variants associated with asthma pathogenesis...
February 24, 2018: Journal of Allergy and Clinical Immunology
Majid Nikpay, Adam W Turner, Ruth McPherson
BACKGROUND: The objective of this study is to investigate the extent and nature of pleiotropy between coronary artery disease (CAD) and body mass index (BMI). METHODS: We examined the contribution of genome-wide single-nucleotide polymorphisms (minor allele frequency ≥0.01) to co-occurrence of CAD and BMI in a sample of genetically unrelated 8041 subjects (genetic resemblance ≤0.025) of European ancestry using mixed-linear-models. We further partitioned the estimated pleiotropy according to biological features to gain insight into the nature of pleiotropy between CAD and BMI...
February 2018: Circ Genom Precis Med
MuhChyi Chai, Tsukasa Sanosaka, Hironobu Okuno, Zhi Zhou, Ikuko Koya, Satoe Banno, Tomoko Andoh-Noda, Yoshikuni Tabata, Rieko Shimamura, Tetsutaro Hayashi, Masashi Ebisawa, Yohei Sasagawa, Itoshi Nikaido, Hideyuki Okano, Jun Kohyama
Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE-neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome...
January 15, 2018: Genes & Development
Nour Ghazzaui, Hussein Issaoui, Alexis Saintamand, Christelle Oblet, Claire Carrion, Yves Denizot
The immunoglobulin heavy chain (IgH) 3' regulatory region (3'RR) superenhancer controls B2 B-cell IgH transcription and cell fate at the mature stage but not early repertoire diversity. B1 B cells represent a small percentage of total B cells differing from B2 B cells by several points such as precursors, development, functions, and regulation. B1 B cells act at the steady state to maintain homeostasis in the organism and during the earliest phases of an immune response, setting them at the interface between innate and acquired immunity...
February 13, 2018: Blood Advances
Telmo Henriques, Benjamin S Scruggs, Michiko O Inouye, Ginger W Muse, Lucy H Williams, Adam B Burkholder, Christopher A Lavender, David C Fargo, Karen Adelman
Regulation by gene-distal enhancers is critical for cell type-specific and condition-specific patterns of gene expression. Thus, to understand the basis of gene activity in a given cell type or tissue, we must identify the precise locations of enhancers and functionally characterize their behaviors. Here, we demonstrate that transcription is a nearly universal feature of enhancers in Drosophila and mammalian cells and that nascent RNA sequencing strategies are optimal for identification of both enhancers and superenhancers...
January 1, 2018: Genes & Development
(no author information available yet)
Ependymoma superenhancer landscapes delineate molecular subgroups and define transcriptional circuitries.
January 12, 2018: Cancer Discovery
Wei Zhong Leong, Shi Hao Tan, Phuong Cao Thi Ngoc, Stella Amanda, Alice Wei Yee Yam, Wei-Siang Liau, Zhiyuan Gong, Lee N Lawton, Daniel G Tenen, Takaomi Sanda
The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lymphoblastic leukemia (T-ALL) cells. However, the critical factors that are directly activated by TAL1 and contribute to T-ALL pathogenesis are largely unknown. Here, we identified AT-rich interactive domain 5B (ARID5B) as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. ARID5B expression is down-regulated at the double-negative 2-4 stages in normal thymocytes, while it is induced by the TAL1 complex in human T-ALL cells...
January 11, 2018: Genes & Development
H Courtney Hodges, Benjamin Z Stanton, Katerina Cermakova, Chiung-Ying Chang, Erik L Miller, Jacob G Kirkland, Wai Lim Ku, Vaclav Veverka, Keji Zhao, Gerald R Crabtree
Mutation of SMARCA4 (BRG1), the ATPase of BAF (mSWI/SNF) and PBAF complexes, contributes to a range of malignancies and neurologic disorders. Unfortunately, the effects of SMARCA4 missense mutations have remained uncertain. Here we show that SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of remodeling. We find that heterozygous expression of mutants alters the open chromatin landscape at thousands of sites across the genome. Loss of DNA accessibility does not directly overlap with Polycomb accumulation, but is enriched in 'A compartments' at active enhancers, which lose H3K27ac but not H3K4me1...
January 2018: Nature Structural & Molecular Biology
Emily K Adler, Rosario I Corona, Janet M Lee, Norma Rodriguez-Malave, Paulette Mhawech-Fauceglia, Heidi Sowter, Dennis J Hazelett, Kate Lawrenson, Simon A Gayther
PAX8 is a lineage-restricted transcription factor that is expressed in epithelial ovarian cancer (EOC) precursor tissues, and in the major EOC histotypes. Frequent overexpression of PAX8 in primary EOCs suggests this factor functions as an oncogene during tumorigenesis, however, the biological role of PAX8 in EOC development is poorly understood. We found that stable knockdown of PAX8 in EOC models significantly reduced cell proliferation and anchorage dependent growth in vitro, and attenuated tumorigenicity in vivo...
December 12, 2017: Oncotarget
Christopher J Ricketts, W Marston Linehan
<b/> Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the von Hippel-Lindau tumor suppressor gene ( VHL ), and the functional tumorigenic consequences of this loss have been used to develop therapies for advanced ccRCC, such as targeting activation of the HIF pathway. Yao and colleagues elucidate how VHL loss contributes to chromatin alteration at both gene promoters and enhancers/superenhancers, in both an HIF-dependent as well as independent manner, and how this may provide additional targets for therapeutic intervention in advanced ccRCC...
November 2017: Cancer Discovery
Peng Li, Suman Mitra, Rosanne Spolski, Jangsuk Oh, Wei Liao, Zhonghui Tang, Fei Mo, Xingwang Li, Erin E West, Daniel Gromer, Jian-Xin Lin, Chengyu Liu, Yijun Ruan, Warren J Leonard
Cytokines critically control immune responses, but how regulatory programs are altered to allow T cells to differentially respond to distinct cytokine stimuli remains poorly understood. Here, we have globally analyzed enhancer elements bound by IL-2-activated STAT5 and IL-21-activated STAT3 in T cells and identified Il2ra as the top-ranked gene regulated by an IL-2-activated STAT5-bound superenhancer and one of the top genes regulated by STAT3-bound superenhancers. Moreover, we found that STAT5 binding was rapidly superenriched at genes highly induced by IL-2 and that IL-2-activated STAT5 binding induces new and augmented chromatin interactions within superenhancer-containing genes...
November 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
Suhas S P Rao, Su-Chen Huang, Brian Glenn St Hilaire, Jesse M Engreitz, Elizabeth M Perez, Kyong-Rim Kieffer-Kwon, Adrian L Sanborn, Sarah E Johnstone, Gavin D Bascom, Ivan D Bochkov, Xingfan Huang, Muhammad S Shamim, Jaeweon Shin, Douglass Turner, Ziyi Ye, Arina D Omer, James T Robinson, Tamar Schlick, Bradley E Bernstein, Rafael Casellas, Eric S Lander, Erez Lieberman Aiden
The human genome folds to create thousands of intervals, called "contact domains," that exhibit enhanced contact frequency within themselves. "Loop domains" form because of tethering between two loci-almost always bound by CTCF and cohesin-lying on the same chromosome. "Compartment domains" form when genomic intervals with similar histone marks co-segregate. Here, we explore the effects of degrading cohesin. All loop domains are eliminated, but neither compartment domains nor histone marks are affected. Loss of loop domains does not lead to widespread ectopic gene activation but does affect a significant minority of active genes...
October 5, 2017: Cell
Eric Wang, Ioannis Aifantis
<b/> In this study, McKeown and colleagues carried out a genome-wide characterization and stratification of the enhancer landscape in acute myeloid leukemia (AML). The authors' analysis led to the discovery of a novel RARA superenhancer found in a subset of patients with AML, rendering these leukemia cells highly sensitive to SY-1425, a highly potent RARA agonist able to induce myeloid differentiation in these high-expressing RARA AML subtypes. Cancer Discov; 7(10); 1065-6. ©2017 AACR. See related article by McKeown et al...
October 2017: Cancer Discovery
Matthew N McCall, Min-Sik Kim, Mohammed Adil, Arun H Patil, Yin Lu, Christopher J Mitchell, Pamela Leal-Rojas, Jinchong Xu, Manoj Kumar, Valina L Dawson, Ted M Dawson, Alexander S Baras, Avi Z Rosenberg, Dan E Arking, Kathleen H Burns, Akhilesh Pandey, Marc K Halushka
MicroRNAs are short RNAs that serve as regulators of gene expression and are essential components of normal development as well as modulators of disease. MicroRNAs generally act cell-autonomously, and thus their localization to specific cell types is needed to guide our understanding of microRNA activity. Current tissue-level data have caused considerable confusion, and comprehensive cell-level data do not yet exist. Here, we establish the landscape of human cell-specific microRNA expression. This project evaluated 8 billion small RNA-seq reads from 46 primary cell types, 42 cancer or immortalized cell lines, and 26 tissues...
October 2017: Genome Research
D B Doroshow, J P Eder, P M LoRusso
Epigenetics has been defined as 'the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states.' Currently, several classes of anticancer drugs function at the epigenetic level, including inhibitors of DNA methyltransferase, histone deacetylase (HDAC), lysine-specific demethylase 1, zeste homolog 2, and bromodomain and extra-terminal motif (BET) proteins.BET proteins have multiple functions, including the initiation and elongation of transcription and cell cycle regulation...
August 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
(no author information available yet)
Superenhancer-associated transcriptional networks promote neuroblastoma heterogeneity.
July 14, 2017: Cancer Discovery
(no author information available yet)
The BET degrader dBET6 induces global BRD4 depletion, whereas JQ1 preferentially affects superenhancers.
July 7, 2017: Cancer Discovery
Alex M Ascensión, Mikel Arrospide-Elgarresta, Ander Izeta, Marcos J Araúzo-Bravo
BACKGROUND: Superenhancers are crucial structural genomic elements determining cell fate, and they are also involved in the determination of several diseases, such as cancer or neurodegeneration. Although there are pipelines which use independent pieces of software to predict the presence of superenhancers from genome-wide chromatin marks or DNA-interaction protein binding sites, there is not yet an integrated software tool that processes automatically algebra combinations of raw data sequencing into a comprehensive final annotated report of predicted superenhancers...
June 6, 2017: BMC Bioinformatics
Jin-Wen Xu, Shuang Ling, Jun Liu
Whether it is caused by viruses and bacteria infection, or low-grade chronic inflammation of atherosclerosis and cellular senescence, the transcription factor (TF) NF-κB plays a central role in the inducible expression of inflammatory genes. Accumulated evidence has indicated that the chromatin environment is the main determinant of TF binding in gene expression regulation, including the stimulus-responsive NF-κB. Dynamic changes in intra- and interchromosomes are the key regulatory mechanisms promoting the binding of TFs...
2017: Mediators of Inflammation
Je Yeong Ko, Sumin Oh, Kyung Hyun Yoo
Tissue-specific transcription is critical for normal development, and abnormalities causing undesirable gene expression may lead to diseases such as cancer. Such highly organized transcription is controlled by enhancers with specific DNA sequences recognized by transcription factors. Enhancers are associated with chromatin modifications that are distinct epigenetic features in a tissue-specific manner. Recently, super-enhancers comprising enhancer clusters co-occupied by lineage-specific factors have been identified in diverse cell types such as adipocytes, hair follicle stem cells, and mammary epithelial cells...
March 2017: Molecules and Cells
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