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Superenhancer

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https://www.readbyqxmd.com/read/29330264/ependymoma-superenhancer-profiling-reveals-potential-therapeutic-targets
#1
(no author information available yet)
Ependymoma superenhancer landscapes delineate molecular subgroups and define transcriptional circuitries.
January 12, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29326336/arid5b-as-a-critical-downstream-target-of-the-tal1-complex-that-activates-the-oncogenic-transcriptional-program-and-promotes-t-cell-leukemogenesis
#2
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
https://www.readbyqxmd.com/read/29323272/dominant-negative-smarca4-mutants-alter-the-accessibility-landscape-of-tissue-unrestricted-enhancers
#3
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
https://www.readbyqxmd.com/read/29312534/the-pax8-cistrome-in-epithelial-ovarian-cancer
#4
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
https://www.readbyqxmd.com/read/29097620/insights-into-epigenetic-remodeling-in-vhl-deficient-clear-cell-renal-cell-carcinoma
#5
Christopher J Ricketts, W Marston Linehan
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
https://www.readbyqxmd.com/read/29078395/stat5-mediated-chromatin-interactions-in-superenhancers-activate-il-2-highly-inducible-genes-functional-dissection-of-the-il2ra-gene-locus
#6
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...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28985562/cohesin-loss-eliminates-all-loop-domains
#7
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
https://www.readbyqxmd.com/read/28974530/targeting-the-noncoding-genome-superenhancers-meet-their-kryptonite
#8
Eric Wang, Ioannis Aifantis
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
https://www.readbyqxmd.com/read/28877962/toward-the-human-cellular-micrornaome
#9
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
https://www.readbyqxmd.com/read/28838216/bet-inhibitors-a-novel-epigenetic-approach
#10
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
https://www.readbyqxmd.com/read/28710101/superenhancers-drive-neuroblastoma-differentiation-states
#11
(no author information available yet)
Superenhancer-associated transcriptional networks promote neuroblastoma heterogeneity.
July 14, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28687569/bet-degradation-is-more-effective-than-competitive-inhibition-in-t-all
#12
(no author information available yet)
The BET degrader dBET6 induces global BRD4 depletion, whereas JQ1 preferentially affects superenhancers.
July 7, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28587674/navise-superenhancer-navigator-integrating-epigenomics-signal-algebra
#13
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
https://www.readbyqxmd.com/read/28490839/higher-order-chromatin-regulation-of-inflammatory-gene-expression
#14
REVIEW
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
https://www.readbyqxmd.com/read/28359147/functional-enhancers-as-master-regulators-of-tissue-specific-gene-regulation-and-cancer-development
#15
REVIEW
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
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/28062474/smarcb1-mutations-disrupt-enhancer-activity-in-rhabdoid-tumors
#17
(no author information available yet)
Loss of the SWI/SNF subunit SMARCB1 disrupts enhancer activation but retains superenhancer activity.
January 6, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/27807035/nucleoporin-mediated-regulation-of-cell-identity-genes
#18
Arkaitz Ibarra, Chris Benner, Swati Tyagi, Jonah Cool, Martin W Hetzer
The organization of the genome in the three-dimensional space of the nucleus is coupled with cell type-specific gene expression. However, how nuclear architecture influences transcription that governs cell identity remains unknown. Here, we show that nuclear pore complex (NPC) components Nup93 and Nup153 bind superenhancers (SE), regulatory structures that drive the expression of key genes that specify cell identity. We found that nucleoporin-associated SEs localize preferentially to the nuclear periphery, and absence of Nup153 and Nup93 results in dramatic transcriptional changes of SE-associated genes...
October 15, 2016: Genes & Development
https://www.readbyqxmd.com/read/27664237/superenhancer-reprogramming-drives-a-b-cell-epithelial-transition-and-high-risk-leukemia
#19
Yeguang Hu, Zhihong Zhang, Mariko Kashiwagi, Toshimi Yoshida, Ila Joshi, Nilamani Jena, Rajesh Somasundaram, Akinola Olumide Emmanuel, Mikael Sigvardsson, Julien Fitamant, Nabeel El-Bardeesy, Fotini Gounari, Richard A Van Etten, Katia Georgopoulos
IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors...
September 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27340176/ino80-governs-superenhancer-mediated-oncogenic-transcription-and-tumor-growth-in-melanoma
#20
Bingying Zhou, Li Wang, Shu Zhang, Brian D Bennett, Fan He, Yan Zhang, Chengliang Xiong, Leng Han, Lixia Diao, Pishun Li, David C Fargo, Adrienne D Cox, Guang Hu
Superenhancers (SEs) are large genomic regions with a high density of enhancer marks. In cancer, SEs are found near oncogenes and dictate cancer gene expression. However, how oncogenic SEs are regulated remains poorly understood. Here, we show that INO80, a chromatin remodeling complex, is required for SE-mediated oncogenic transcription and tumor growth in melanoma. The expression of Ino80, the SWI/SNF ATPase, is elevated in melanoma cells and patient melanomas compared with normal melanocytes and benign nevi...
June 15, 2016: Genes & Development
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