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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
(no author information available yet)
Loss of the SWI/SNF subunit SMARCB1 disrupts enhancer activation but retains superenhancer activity.
January 6, 2017: Cancer Discovery
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
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
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
Omer Gilan, Enid Y N Lam, Isabelle Becher, Dave Lugo, Ester Cannizzaro, Gerard Joberty, Aoife Ward, Meike Wiese, Chun Yew Fong, Sarah Ftouni, Dean Tyler, Kym Stanley, Laura MacPherson, Chen-Fang Weng, Yih-Chih Chan, Margherita Ghisi, David Smil, Christopher Carpenter, Peter Brown, Neil Garton, Marnie E Blewitt, Andrew J Bannister, Tony Kouzarides, Brian J P Huntly, Ricky W Johnstone, Gerard Drewes, Sarah-Jane Dawson, Cheryl H Arrowsmith, Paola Grandi, Rab K Prinjha, Mark A Dawson
Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models...
July 2016: Nature Structural & Molecular Biology
Mark Y Chiang, Vedran Radojcic, Ivan Maillard
PURPOSE OF REVIEW: This article highlights recent discoveries about Notch activation and its oncogenic functions in lymphoid malignancies, and discusses the therapeutic potential of Notch inhibition. RECENT FINDINGS: NOTCH mutations arise in a broad spectrum of lymphoid malignancies and are increasingly scrutinized as putative therapeutic targets. In T-cell acute lymphoblastic leukemia (T-ALL), NOTCH1 mutations affect the extracellular negative regulatory region and lead to constitutive Notch activation, although mutated receptors remain sensitive to Notch ligands...
July 2016: Current Opinion in Hematology
Paloma Cejas, Lewyn Li, Nicholas K O'Neill, Melissa Duarte, Prakash Rao, Michaela Bowden, Chensheng W Zhou, Marta Mendiola, Emilio Burgos, Jaime Feliu, Juan Moreno-Rubio, Héctor Guadalajara, Víctor Moreno, Damián García-Olmo, Joaquim Bellmunt, Stephanie Mullane, Michelle Hirsch, Christopher J Sweeney, Andrea Richardson, X Shirley Liu, Myles Brown, Ramesh A Shivdasani, Henry W Long
Extensive cross-linking introduced during routine tissue fixation of clinical pathology specimens severely hampers chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) analysis from archived tissue samples. This limits the ability to study the epigenomes of valuable, clinically annotated tissue resources. Here we describe fixed-tissue chromatin immunoprecipitation sequencing (FiT-seq), a method that enables reliable extraction of soluble chromatin from formalin-fixed paraffin-embedded (FFPE) tissue samples for accurate detection of histone marks...
June 2016: Nature Medicine
Mark L McCleland, Kathryn Mesh, Edward Lorenzana, Vivek S Chopra, Ehud Segal, Colin Watanabe, Benjamin Haley, Oleg Mayba, Murat Yaylaoglu, Florian Gnad, Ron Firestein
Colon tumors arise in a stepwise fashion from either discrete genetic perturbations or epigenetic dysregulation. To uncover the key epigenetic regulators that drive colon cancer growth, we used a CRISPR loss-of-function screen and identified a number of essential genes, including the bromodomain and extraterminal (BET) protein BRD4. We found that BRD4 is critical for colon cancer proliferation, and its knockdown led to differentiation effects in vivo. JQ1, a BET inhibitor, preferentially reduced growth in a subset of epigenetically dysregulated colon cancers characterized by the CpG island methylator phenotype (CIMP)...
February 2016: Journal of Clinical Investigation
Emma K Farley, Katrina M Olson, Wei Zhang, Alexander J Brandt, Daniel S Rokhsar, Michael S Levine
Transcriptional enhancers direct precise on-off patterns of gene expression during development. To explore the basis for this precision, we conducted a high-throughput analysis of the Otx-a enhancer, which mediates expression in the neural plate of Ciona embryos in response to fibroblast growth factor (FGF) signaling and a localized GATA determinant. We provide evidence that enhancer specificity depends on submaximal recognition motifs having reduced binding affinities ("suboptimization"). Native GATA and ETS (FGF) binding sites contain imperfect matches to consensus motifs...
October 16, 2015: Science
(no author information available yet)
YAP occupies a subset of highly active enhancers and regulates RNA Pol II pause release.
December 2015: Cancer Discovery
Giorgio G Galli, Matteo Carrara, Wei-Chien Yuan, Christian Valdes-Quezada, Basanta Gurung, Brian Pepe-Mooney, Tinghu Zhang, Geert Geeven, Nathanael S Gray, Wouter de Laat, Raffaele A Calogero, Fernando D Camargo
The Hippo/YAP signaling pathway is a crucial regulator of tissue growth, stem cell activity, and tumorigenesis. However, the mechanism by which YAP controls transcription remains to be fully elucidated. Here, we utilize global chromatin occupancy analyses to demonstrate that robust YAP binding is restricted to a relatively small number of distal regulatory elements in the genome. YAP occupancy defines a subset of enhancers and superenhancers with the highest transcriptional outputs. YAP modulates transcription from these elements predominantly by regulating promoter-proximal polymerase II (Pol II) pause release...
October 15, 2015: Molecular Cell
Gary E Grajales-Reyes, Arifumi Iwata, Jörn Albring, Xiaodi Wu, Roxane Tussiwand, Wumesh Kc, Nicole M Kretzer, Carlos G Briseño, Vivek Durai, Prachi Bagadia, Malay Haldar, Jörg Schönheit, Frank Rosenbauer, Theresa L Murphy, Kenneth M Murphy
The transcription factors Batf3 and IRF8 are required for the development of CD8α(+) conventional dendritic cells (cDCs), but the basis for their actions has remained unclear. Here we identified two progenitor cells positive for the transcription factor Zbtb46 that separately generated CD8α(+) cDCs and CD4(+) cDCs and arose directly from the common DC progenitor (CDP). Irf8 expression in CDPs required prior autoactivation of Irf8 that was dependent on the transcription factor PU.1. Specification of the clonogenic progenitor of CD8α(+) cDCs (the pre-CD8 DC) required IRF8 but not Batf3...
July 2015: Nature Immunology
Matthew J Harms, Hee-Woong Lim, Yugong Ho, Suzanne N Shapira, Jeff Ishibashi, Sona Rajakumari, David J Steger, Mitchell A Lazar, Kyoung-Jae Won, Patrick Seale
PR (PRD1-BF1-RIZ1 homologous) domain-containing 16 (PRDM16) drives a brown fat differentiation program, but the mechanisms by which PRDM16 activates brown fat-selective genes have been unclear. Through chromatin immunoprecipitation (ChIP) followed by deep sequencing (ChIP-seq) analyses in brown adipose tissue (BAT), we reveal that PRDM16 binding is highly enriched at a broad set of brown fat-selective genes. Importantly, we found that PRDM16 physically binds to MED1, a component of the Mediator complex, and recruits it to superenhancers at brown fat-selective genes...
February 1, 2015: Genes & Development
Abhishek Sohni, Michela Bartoccetti, Rita Khoueiry, Lien Spans, Joris Vande Velde, Linde De Troyer, Kirthi Pulakanti, Frank Claessens, Sridhar Rao, Kian Peng Koh
The Tet 5-methylcytosine dioxygenases catalyze DNA demethylation by producing 5-hydroxymethylcytosine and further oxidized products. Tet1 and Tet2 are highly expressed in mouse pluripotent cells and downregulated to different extents in somatic cells, but the transcriptional mechanisms are unclear. Here we defined the promoter and enhancer domains in Tet1 and Tet2. Within a 15-kb "superenhancer" of Tet1, there are two transcription start sites (TSSs) with different activation patterns during development. A 6-kb promoter region upstream of the distal TSS is highly active in naive pluripotent cells, autonomously reports Tet1 expression in a transgenic system, and rapidly undergoes DNA methylation and silencing upon differentiation in cultured cells and native epiblast...
March 2015: Molecular and Cellular Biology
Tural Khudiyev, Mehmet Bayindir
Nanowires play a crucial role in the development of new generation optoelectronic devices ranging from photovoltaics to photodetectors, as these designs capitalize on the low material usage, utilize leaky-mode optical resonances and possess high conversion efficiencies associated with nanowire geometry. However, their current schemes lack sufficient absorption capacity demanded for their practical applicability, and more efficient materials cannot find widespread usage in these designs due to their rarity and cost...
2014: Scientific Reports
Anne Loft, Isabel Forss, Majken Storm Siersbæk, Søren Fisker Schmidt, Ann-Sofie Bøgh Larsen, Jesper Grud Skat Madsen, Didier F Pisani, Ronni Nielsen, Mads Malik Aagaard, Angela Mathison, Matt J Neville, Raul Urrutia, Fredrik Karpe, Ez-Zoubir Amri, Susanne Mandrup
Long-term exposure to peroxisome proliferator-activated receptor γ (PPARγ) agonists such as rosiglitazone induces browning of rodent and human adipocytes; however, the transcriptional mechanisms governing this phenotypic switch in adipocytes are largely unknown. Here we show that rosiglitazone-induced browning of human adipocytes activates a comprehensive gene program that leads to increased mitochondrial oxidative capacity. Once induced, this gene program and oxidative capacity are maintained independently of rosiglitazone, suggesting that additional browning factors are activated...
January 1, 2015: Genes & Development
Chia-Pin Liang, Takahito Nakajima, Rira Watanabe, Kazuhide Sato, Peter L Choyke, Yu Chen, Hisataka Kobayashi
Photoimmunotherapy (PIT) is a cell-specific cancer therapy based on an armed antibody conjugate that induces rapid and highly selective cancer cell necrosis after exposure to near-infrared (NIR) light. The PIT treatment also induces the superenhanced permeability and retention effect, which allows high concentrations of nanoparticles to accumulate in the tumor bed. In our pilot studies, optical coherence tomography (OCT) reveals dramatic hemodynamic changes during PIT. We developed and applied speckle variance analysis, Doppler flow measurement, bulk motion removal, and automatic region of interest selection to quantify vessel diameter and blood velocity within tumors in vivo...
September 2014: Journal of Biomedical Optics
Yosef Buganim, Styliani Markoulaki, Niek van Wietmarschen, Heather Hoke, Tao Wu, Kibibi Ganz, Batool Akhtar-Zaidi, Yupeng He, Brian J Abraham, David Porubsky, Elisabeth Kulenkampff, Dina A Faddah, Linyu Shi, Qing Gao, Sovan Sarkar, Malkiel Cohen, Johanna Goldmann, Joseph R Nery, Matthew D Schultz, Joseph R Ecker, Andrew Xiao, Richard A Young, Peter M Lansdorp, Rudolf Jaenisch
Induced pluripotent stem cells (iPSCs) are commonly generated by transduction of Oct4, Sox2, Klf4, and Myc (OSKM) into cells. Although iPSCs are pluripotent, they frequently exhibit high variation in terms of quality, as measured in mice by chimera contribution and tetraploid complementation. Reliably high-quality iPSCs will be needed for future therapeutic applications. Here, we show that one major determinant of iPSC quality is the combination of reprogramming factors used. Based on tetraploid complementation, we found that ectopic expression of Sall4, Nanog, Esrrb, and Lin28 (SNEL) in mouse embryonic fibroblasts (MEFs) generated high-quality iPSCs more efficiently than other combinations of factors including OSKM...
September 4, 2014: Cell Stem Cell
Andrew L Wolfe, Kamini Singh, Yi Zhong, Philipp Drewe, Vinagolu K Rajasekhar, Viraj R Sanghvi, Konstantinos J Mavrakis, Man Jiang, Justine E Roderick, Joni Van der Meulen, Jonathan H Schatz, Christina M Rodrigo, Chunying Zhao, Pieter Rondou, Elisa de Stanchina, Julie Teruya-Feldstein, Michelle A Kelliher, Frank Speleman, John A Porco, Jerry Pelletier, Gunnar Rätsch, Hans-Guido Wendel
The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo...
September 4, 2014: Nature
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