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https://www.readbyqxmd.com/read/28601576/real-time-monitoring-of-microdistribution-of-antibody-photon-absorber-conjugates-during-photoimmunotherapy-in-vivo
#1
Qinggong Tang, Tadanobu Nagaya, Yi Liu, Jonathan Lin, Kazuhide Sato, Hisataka Kobayashi, Yu Chen
Photoimmunotherapy (PIT) is an emerging low side effect cancer therapy based on a monoclonal antibody (mAb) conjugated with a near-infrared (NIR) phthalocyanine dye IRDye 700DX. IR700 is fluorescent, can be used as an imaging agent, and also is phototoxic. It induces rapid cell death after exposure to NIR light. PIT induces highly selective cancer cell death, while leaving most of tumor blood vessels unharmed, leading to an effect called super-enhanced permeability and retention (SUPR). SUPR significantly improves the effectiveness of the anticancer drug...
June 8, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28583252/mice-deficient-of-myc-super-enhancer-region-reveal-differential-control-mechanism-between-normal-and-pathological-growth
#2
Kashyap Dave, Inderpreet Sur, Jian Yan, Jilin Zhang, Eevi Kaasinen, Fan Zhong, Leander Blaas, Xiaoze Li, Shabnam Kharazi, Charlotte Gustafsson, Ayla De Paepe, Robert Månsson, Jussi Taipale
The gene desert upstream of the MYC oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50% to 80% decrease in Myc expression in multiple tissues. The mice are viable and show no overt phenotype...
June 6, 2017: ELife
https://www.readbyqxmd.com/read/28576751/targeting-of-super-enhancers-and-mutant-braf-can-suppress-growth-of-braf-mutant-colon-cancer-cells-via-repression-of-mapk-signaling-pathway
#3
Yoshiaki Nakamura, Naoko Hattori, Naoko Iida, Satoshi Yamashita, Akiko Mori, Kana Kimura, Takayuki Yoshino, Toshikazu Ushijima
Bromodomain and extra-terminal (BET) inhibitors suppress super-enhancers and show cytotoxicity against multiple types of tumors. However, early clinical trials with BET inhibitors showed severe hematopoietic toxicities, highlighting the need for sensitive tumors and rational combination strategies to enhance their therapeutic potential. Here, we identified colon cancer-specific super-enhancers that were associated with multiple oncogenic pathways, including the mitogen-activated protein kinase (MAPK) signaling pathway...
May 31, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28575289/myod-and-foxo3-mediated-hotspot-interaction-orchestrates-super-enhancer-activity-during-myogenic-differentiation
#4
Xianlu L Peng, Karl K So, Liangqiang He, Yu Zhao, Jiajian Zhou, Yuying Li, Mingze Yao, Bo Xu, Suyang Zhang, Hongjie Yao, Ping Hu, Hao Sun, Huating Wang
Super-enhancers (SEs) are cis-regulatory elements enriching lineage specific key transcription factors (TFs) to form hotspots. A paucity of identification and functional dissection promoted us to investigate SEs during myoblast differentiation. ChIP-seq analysis of histone marks leads to the uncovering of SEs which remodel progressively during the course of differentiation. Further analyses of TF ChIP-seq enable the definition of SE hotspots co-bound by the master TF, MyoD and other TFs, among which we perform in-depth dissection for MyoD/FoxO3 interaction in driving the hotspots formation and SE activation...
June 1, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28572168/preclinical-efficacy-and-molecular-mechanism-of-targeting-cdk7-dependent-transcriptional-addiction-in-ovarian-cancer
#5
Zhenfeng Zhang, Huixin Peng, Xiaojie Wang, Xia Yin, Pengfei Ma, Ying Jing, Mei-Chun Cai, Jin Liu, Meiying Zhang, Shengzhe Zhang, Kaixuan Shi, Wei-Qiang Gao, Wen Di, Guanglei Zhuang
Ovarian cancer remains a significant cause of gynecological cancer mortality and novel therapeutic strategies are urgently needed in clinic as new treatment options. We previously showed that BET bromodomain inhibitors displayed promising efficacy for the treatment of epithelial ovarian cancer by downregulating pivot transcription factors. However, the potential anti-tumor activities and molecular mechanisms of other epigenetic or transcriptional therapies have not been systematically determined. Here, by performing an unbiased high-throughput drug screen to identify candidate compounds with antineoplastic effects, we identified THZ1, a recently developed covalent CDK7 inhibitor, as a new transcription-targeting compound that exerted broad cytotoxicity against ovarian tumors...
June 1, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28530713/bach2-immunodeficiency-illustrates-an-association-between-super-enhancers-and-haploinsufficiency
#6
Behdad Afzali, Juha Grönholm, Jana Vandrovcova, Charlotte O'Brien, Hong-Wei Sun, Ine Vanderleyden, Fred P Davis, Ahmad Khoder, Yu Zhang, Ahmed N Hegazy, Alejandro V Villarino, Ira W Palmer, Joshua Kaufman, Norman R Watts, Majid Kazemian, Olena Kamenyeva, Julia Keith, Anwar Sayed, Dalia Kasperaviciute, Michael Mueller, Jason D Hughes, Ivan J Fuss, Mohammed F Sadiyah, Kim Montgomery-Recht, Joshua McElwee, Nicholas P Restifo, Warren Strober, Michelle A Linterman, Paul T Wingfield, Holm H Uhlig, Rahul Roychoudhuri, Timothy J Aitman, Peter Kelleher, Michael J Lenardo, John J O'Shea, Nichola Cooper, Arian D J Laurence
The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency...
July 2017: Nature Immunology
https://www.readbyqxmd.com/read/28526829/super-enhancers-and-broad-h3k4me3-domains-form-complex-gene-regulatory-circuits-involving-chromatin-interactions
#7
Fan Cao, Yiwen Fang, Hong Kee Tan, Yufen Goh, Jocelyn Yeen Hui Choy, Bryan Thean Howe Koh, Jiong Hao Tan, Nicolas Bertin, Aroul Ramadass, Ewan Hunter, Jayne Green, Matthew Salter, Alexandre Akoulitchev, Wilson Wang, Wee Joo Chng, Daniel G Tenen, Melissa J Fullwood
Stretched histone regions, such as super-enhancers and broad H3K4me3 domains, are associated with maintenance of cell identity and cancer. We connected super-enhancers and broad H3K4me3 domains in the K562 chronic myelogenous leukemia cell line as well as the MCF-7 breast cancer cell line with chromatin interactions. Super-enhancers and broad H3K4me3 domains showed higher association with chromatin interactions than their typical counterparts. Interestingly, we identified a subset of super-enhancers that overlap with broad H3K4me3 domains and show high association with cancer-associated genes including tumor suppressor genes...
May 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28505376/evolutionary-re-wiring-of-p63-and-the-epigenomic-regulatory-landscape-in-keratinocytes-and-its-potential-implications-on-species-specific-gene-expression-and-phenotypes
#8
Isha Sethi, Christian Gluck, Huiqing Zhou, Michael J Buck, Satrajit Sinha
Although epidermal keratinocyte development and differentiation proceeds in similar fashion between humans and mice, evolutionary pressures have also wrought significant species-specific physiological differences. These differences between species could arise in part, by the rewiring of regulatory network due to changes in the global targets of lineage-specific transcriptional master regulators such as p63. Here we have performed a systematic and comparative analysis of the p63 target gene network within the integrated framework of the transcriptomic and epigenomic landscape of mouse and human keratinocytes...
May 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28494871/mirna-32-drives-brown-fat-thermogenesis-and-trans-activates-subcutaneous-white-fat-browning-in-mice
#9
Raymond Ng, Nurul Attiqah Hussain, Qiongyi Zhang, Chengwei Chang, Hongyu Li, Yanyun Fu, Lei Cao, Weiping Han, Walter Stunkel, Feng Xu
Brown adipose tissue (BAT) activation and subcutaneous white fat browning are essential components of the thermogenic response to cold stimulus in mammals. microRNAs have been shown to regulate both processes in cis. Here, we identify miR-32 as a BAT-specific super-enhancer-associated miRNA in mice that is selectively expressed in BAT and further upregulated during cold exposure. Inhibiting miR-32 in vivo led to impaired cold tolerance, decreased BAT thermogenesis, and compromised white fat browning as a result of reduced serum FGF21 levels...
May 9, 2017: Cell Reports
https://www.readbyqxmd.com/read/28494239/crispr-cas9-screens-reveal-epstein-barr-virus-transformed-b-cell-host-dependency-factors
#10
Yijie Ma, Michael J Walsh, Katharina Bernhardt, Camille W Ashbaugh, Stephen J Trudeau, Isabelle Y Ashbaugh, Sizun Jiang, Chang Jiang, Bo Zhao, David E Root, John G Doench, Benjamin E Gewurz
Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma (BL) and immunosuppression-related lymphomas. These B cell malignancies arise by distinct transformation pathways and have divergent viral and host expression programs. To identify host dependency factors resulting from these EBV+, B cell-transformed cell states, we performed parallel genome-wide CRISPR/Cas9 loss-of-function screens in BL and lymphoblastoid cell lines (LCLs). These highlighted 57 BL and 87 LCL genes uniquely important for their growth and survival...
May 10, 2017: Cell Host & Microbe
https://www.readbyqxmd.com/read/28486100/using-epigenetic-reprogramming-to-treat-pediatric-brain-cancer
#11
Milan G Chheda, David H Gutmann
In this issue of Cancer Cell, Nagaraja et al. dissect the molecular mechanisms underlying therapeutic responses to transcriptional disruptors in the fatal pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). Moreover, they identify super-enhancers mediating these effects, highlighting how normal brain developmental programs can be hijacked in cancer.
May 8, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28472656/the-dynamic-epigenetic-landscape-of-the-retina-during-development-reprogramming-and-tumorigenesis
#12
Issam Aldiri, Beisi Xu, Lu Wang, Xiang Chen, Daniel Hiler, Lyra Griffiths, Marc Valentine, Abbas Shirinifard, Suresh Thiagarajan, Andras Sablauer, Marie-Elizabeth Barabas, Jiakun Zhang, Dianna Johnson, Sharon Frase, Xin Zhou, John Easton, Jinghui Zhang, Elaine R Mardis, Richard K Wilson, James R Downing, Michael A Dyer
In the developing retina, multipotent neural progenitors undergo unidirectional differentiation in a precise spatiotemporal order. Here we profile the epigenetic and transcriptional changes that occur during retinogenesis in mice and humans. Although some progenitor genes and cell cycle genes were epigenetically silenced during retinogenesis, the most dramatic change was derepression of cell-type-specific differentiation programs. We identified developmental-stage-specific super-enhancers and showed that most epigenetic changes are conserved in humans and mice...
May 3, 2017: Neuron
https://www.readbyqxmd.com/read/28467369/developmental-control-of-nramp1-slc11a1-expression-in-professional-phagocytes
#13
Mathieu F M Cellier
NRAMP1 (SLC11A1) is a professional phagocyte membrane importer of divalent metals that contributes to iron recycling at homeostasis and to nutritional immunity against infection. Analyses of data generated by several consortia and additional studies were integrated to hypothesize mechanisms restricting NRAMP1 expression to mature phagocytes. Results from various epigenetic and transcriptomic approaches were collected for mesodermal and hematopoietic cell types and compiled for combined analysis with results of genetic studies associating single nucleotide polymorphisms (SNPs) with variations in NRAMP1 expression (eQTLs)...
May 3, 2017: Biology
https://www.readbyqxmd.com/read/28463873/transcriptional-circuits-in-b-cell-transformation
#14
Yeguang Hu, Toshimi Yoshida, Katia Georgopoulos
PURPOSE OF REVIEW: Loss of IKAROS in committed B cell precursors causes a block in differentiation while at the same time augments aberrant cellular properties, such as bone marrow stromal adhesion, self-renewal and resistance to glucocorticoid-mediated cell death. B cell acute lymphoblastic leukaemias originating from these early stages of B cell differentiation and associated with IKAROS mutations share a high-risk cellular phenotype suggesting that deregulation of IKAROS-based mechanisms cause a highly malignant disease process...
July 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28456784/near-infrared-photoimmunotherapy-a-comparison-of-light-dosing-schedules
#15
Fusa Ogata, Tadanobu Nagaya, Yuko Nakamura, Kazuhide Sato, Shuhei Okuyama, Yasuhiro Maruoka, Peter L Choyke, Hisataka Kobayashi
Near infrared photoimmunotherapy (NIR-PIT) is a newly-developed cancer therapy in which a monoclonal antibody is conjugated to a near-infrared photoabsorber, IR700 to form an antibody photoabsorber conjugate (APC). After the APC binds to cancer cells expressing the cognate antigen, exposure to NIR light results in rapid, highly selective necrotic cell death of the cancer cells with minimal off-target effects. Several hours after NIR-PIT, the tumor vessels become supraphysiologically permeable and circulating APC can therefore readily leak into the already-treated tumor space where it can bind with viable cancer cells that is called super-enhanced permeability and retention effect...
May 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28446439/pax3-foxo1-establishes-myogenic-super-enhancers-and-confers-bet-bromodomain-vulnerability
#16
Berkley E Gryder, Marielle E Yohe, Hsien-Chao Chou, Xiaohu Zhang, Joana Marques, Marco Wachtel, Beat Schaefer, Nirmalya Sen, Young K Song, Alberto Gualtieri, Silvia Pomella, Rossella Rota, Abigail Cleveland, Xinyu Wen, Sivasish Sindiri, Jun S Wei, Frederic G Barr, Sudipto Das, Thorkell Andresson, Rajarshi Guha, Madhu Lal-Nag, Marc Ferrer, Jack F Shern, Keji Zhao, Craig J Thomas, Javed Khan
Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1 (P3F). The mechanisms by which P3F dysregulates chromatin are unknown. We find P3F reprograms the cis-regulatory landscape by inducing (de novo) super enhancers (SEs). P3F uses SEs to setup auto-regulatory loops in collaboration with master transcription factors MYOG, MYOD and MYCN. This myogenic SE circuitry is consistent across cell lines and primary tumors...
April 26, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28445475/grhl3-binding-and-enhancers-rearrange-as-epidermal-keratinocytes-transition-between-functional-states
#17
Rachel Herndon Klein, Ziguang Lin, Amelia Soto Hopkin, William Gordon, Lam C Tsoi, Yun Liang, Johann E Gudjonsson, Bogi Andersen
Transcription factor binding, chromatin modifications and large scale chromatin re-organization underlie progressive, irreversible cell lineage commitments and differentiation. We know little, however, about chromatin changes as cells enter transient, reversible states such as migration. Here we demonstrate that when human progenitor keratinocytes either differentiate or migrate they form complements of typical enhancers and super-enhancers that are unique for each state. Unique super-enhancers for each cellular state link to gene expression that confers functions associated with the respective cell state...
April 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28434841/transcriptional-dependencies-in-diffuse-intrinsic-pontine-glioma
#18
Surya Nagaraja, Nicholas A Vitanza, Pamelyn J Woo, Kathryn R Taylor, Fang Liu, Lei Zhang, Meng Li, Wei Meng, Anitha Ponnuswami, Wenchao Sun, Jie Ma, Esther Hulleman, Tomek Swigut, Joanna Wysocka, Yujie Tang, Michelle Monje
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade...
May 8, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28420548/expression-of-long-non-coding-rnas-in-autoimmunity-and-linkage-to-enhancer-function-and-autoimmune-disease-risk-genetic-variants
#19
T M Aune, P S Crooke, A E Patrick, J T Tossberg, N J Olsen, C F Spurlock
Genome-wide association studies have identified numerous genetic variants conferring autoimmune disease risk. Most of these genetic variants lie outside protein-coding genes hampering mechanistic explorations. Numerous mRNAs are also differentially expressed in autoimmune disease but their regulation is also unclear. The majority of the human genome is transcribed yet its biologic significance is incompletely understood. We performed whole genome RNA-sequencing [RNA-seq] to categorize expression of mRNAs, known and novel long non-coding RNAs [lncRNAs] in leukocytes from subjects with autoimmune disease and identified annotated and novel lncRNAs differentially expressed across multiple disorders...
July 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28416141/multiplexed-engineering-and-analysis-of-combinatorial-enhancer-activity-in-single-cells
#20
Shiqi Xie, Jialei Duan, Boxun Li, Pei Zhou, Gary C Hon
The study of enhancers has been hampered by the scarcity of methods to systematically quantify their endogenous activity. We develop Mosaic-seq to systematically perturb enhancers and measure their endogenous activities at single-cell resolution. Mosaic-seq uses a CRISPR barcoding system to jointly measure a cell's transcriptome and its sgRNA modulators, thus quantifying the effects of dCas9-KRAB-mediated enhancer repression in single cells. Applying Mosaic-seq to 71 constituent enhancers from 15 super-enhancers, our analysis of 51,448 sgRNA-induced transcriptomes finds that only a small number of constituents are major effectors of target gene expression...
April 20, 2017: Molecular Cell
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