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Philipp G Maass, A Rasim Barutcu, Catherine L Weiner, John L Rinn
Imaging (fluorescence in situ hybridization [FISH]) and genome-wide chromosome conformation capture (Hi-C) are two major approaches to the study of higher-order genome organization in the nucleus. Intra-chromosomal and inter-chromosomal interactions (referred to as non-homologous chromosomal contacts [NHCCs]) have been observed by several FISH-based studies, but locus-specific NHCCs have not been detected by Hi-C. Due to crosslinking, neither of these approaches assesses spatiotemporal properties. Toward resolving the discrepancies between imaging and Hi-C, we sought to understand the spatiotemporal properties of NHCCs in living cells by CRISPR/Cas9 live-cell imaging (CLING)...
February 27, 2018: Molecular Cell
Julie Donaghey, Sudhir Thakurela, Jocelyn Charlton, Jennifer S Chen, Zachary D Smith, Hongcang Gu, Ramona Pop, Kendell Clement, Elena K Stamenova, Rahul Karnik, David R Kelley, Casey A Gifford, Davide Cacchiarelli, John L Rinn, Andreas Gnirke, Michael J Ziller, Alexander Meissner
Transcription factors (TFs) direct developmental transitions by binding to target DNA sequences, influencing gene expression and establishing complex gene-regultory networks. To systematically determine the molecular components that enable or constrain TF activity, we investigated the genomic occupancy of FOXA2, GATA4 and OCT4 in several cell types. Despite their classification as pioneer factors, all three TFs exhibit cell-type-specific binding, even when supraphysiologically and ectopically expressed. However, FOXA2 and GATA4 can be distinguished by low enrichment at loci that are highly occupied by these factors in alternative cell types...
January 22, 2018: Nature Genetics
Philipp G Maass, A Rasim Barutcu, David M Shechner, Catherine L Weiner, Marta Melé, John L Rinn
Imaging and chromatin capture techniques have provided important insights into our understanding of nuclear organization. A limitation of these techniques is the inability to resolve allele-specific spatiotemporal properties of genomic loci in living cells. Here, we describe an allele-specific CRISPR live-cell DNA imaging technique (SNP-CLING) to provide the first comprehensive insights into allelic positioning across space and time in mouse embryonic stem cells and fibroblasts. With 3D imaging, we studied alleles on different chromosomes in relation to one another and relative to nuclear substructures such as the nucleolus...
January 8, 2018: Nature Structural & Molecular Biology
Chinmay J Shukla, Alexandra L McCorkindale, Chiara Gerhardinger, Keegan D Korthauer, Moran N Cabili, David M Shechner, Rafael A Irizarry, Philipp G Maass, John L Rinn
In the post-genomic era, thousands of putative noncoding regulatory regions have been identified, such as enhancers, promoters, long noncoding RNAs (lncRNAs), and a cadre of small peptides. These ever-growing catalogs require high-throughput assays to test their functionality at scale. Massively parallel reporter assays have greatly enhanced the understanding of noncoding DNA elements en masse Here, we present a massively parallel RNA assay (MPRNA) that can assay 10,000 or more RNA segments for RNA-based functionality...
January 15, 2018: EMBO Journal
Pornchai Kaewsapsak, David Michael Shechner, William Mallard, John L Rinn, Alice Y Ting
The spatial organization of RNA within cells is a crucial factor influencing a wide range of biological functions throughout all kingdoms of life. However, a general understanding of RNA localization has been hindered by a lack of simple, high-throughput methods for mapping the transcriptomes of subcellular compartments. Here, we develop such a method, termed APEX-RIP, which combines peroxidase-catalyzed, spatially restricted in situ protein biotinylation with RNA-protein chemical crosslinking. We demonstrate that, using a single protocol, APEX-RIP can isolate RNAs from a variety of subcellular compartments, including the mitochondrial matrix, nucleus, cytosol, and endoplasmic reticulum (ER), with specificity and sensitivity that rival or exceed those of conventional approaches...
December 14, 2017: ELife
Willemijn J Jansen, Rik Ossenkoppele, Betty M Tijms, Anne M Fagan, Oskar Hansson, William E Klunk, Wiesje M van der Flier, Victor L Villemagne, Giovanni B Frisoni, Adam S Fleisher, Alberto Lleó, Mark A Mintun, Anders Wallin, Sebastiaan Engelborghs, Duk L Na, Gäel Chételat, José Luis Molinuevo, Susan M Landau, Niklas Mattsson, Johannes Kornhuber, Osama Sabri, Christopher C Rowe, Lucilla Parnetti, Julius Popp, Tormod Fladby, William J Jagust, Pauline Aalten, Dong Young Lee, Rik Vandenberghe, Catarina Resende de Oliveira, Elisabeth Kapaki, Lutz Froelich, Adrian Ivanoiu, Tomasz Gabryelewicz, Marcel M Verbeek, Páscual Sanchez-Juan, Helmut Hildebrandt, Vincent Camus, Marzena Zboch, David J Brooks, Alexander Drzezga, Juha O Rinne, Andrew Newberg, Alexandre de Mendonça, Marie Sarazin, Gil D Rabinovici, Karine Madsen, Milica G Kramberger, Agneta Nordberg, Vincent Mok, Barbara Mroczko, David A Wolk, Philipp T Meyer, Magda Tsolaki, Philip Scheltens, Frans R J Verhey, Pieter Jelle Visser, Dag Aarsland, Daniel Alcolea, Myriam Alexander, Ina S Almdahl, Steven E Arnold, Inês Baldeiras, Henryk Barthel, Bart N M van Berckel, Kaj Blennow, Mark A van Buchem, Enrica Cavedo, Kewei Chen, Elena Chipi, Ann D Cohen, Stefan Förster, Juan Fortea, Kristian S Frederiksen, Yvonne Freund-Levi, Olymbia Gkatzima, Mark Forrest Gordon, Timo Grimmer, Harald Hampel, Lucrezia Hausner, Sabine Hellwig, Sanna-Kaisa Herukka, Peter Johannsen, Aleksandra Klimkowicz-Mrowiec, Sebastian Köhler, Norman Koglin, Koen van Laere, Mony de Leon, Viviana Lisetti, Wolfgang Maier, Jan Marcusson, Olga Meulenbroek, Hanne M Møllergård, John C Morris, Arto Nordlund, Gerald P Novak, George P Paraskevas, Gayan Perera, Oliver Peters, Inez H G B Ramakers, Lorena Rami, Eloy Rodríguez-Rodríguez, Catherine M Roe, Uros Rot, Eckart Rüther, Isabel Santana, Johannes Schröder, Sang W Seo, Hilkka Soininen, Luiza Spiru, Erik Stomrud, Hanne Struyfs, Charlotte E Teunissen, Stephanie J B Vos, Linda J C van Waalwijk van Doorn, Gunhild Waldemar, Åsa K Wallin, Jens Wiltfang, Henrik Zetterberg
Importance: Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. Objective: To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study...
January 1, 2018: JAMA Psychiatry
Maria Rosestedt, Ken G Andersson, Bogdan Mitran, Sara S Rinne, Vladimir Tolmachev, John Löfblom, Anna Orlova, Stefan Ståhl
The human epidermal growth factor receptor 3 (HER3) is involved in the development of cancer resistance towards tyrosine kinase-targeted therapies. Several HER3‑targeting therapeutics are currently under clinical evaluation. Non-invasive imaging of HER3 expression could improve patient management. Affibody molecules are small engineered scaffold proteins demonstrating superior properties as targeting probes for molecular imaging compared with monoclonal antibodies. Feasibility of in vivo HER3 imaging using affibody molecules has been previously demonstrated...
October 11, 2017: International Journal of Oncology
Scott T Younger, John L Rinn
The tumor suppressor p53 is a well-characterized transcription factor that can bind gene promoters and regulate target gene transcription in response to DNA damage. Recent studies, however, have revealed that p53 binding events occur predominantly within regulatory enhancer elements. The effect of p53 binding on enhancer function has not been systematically evaluated. Here, we perform a genome-scale analysis of enhancer activity from p53-bound sequences using a series of massively parallel reporter assays (MPRAs) coupled with the assay for transposase-accessible chromatin (ATAC-Seq)...
September 29, 2017: Nucleic Acids Research
Walter K Mowel, Sam J McCright, Jonathan J Kotzin, Magalie A Collet, Asli Uyar, Xin Chen, Alexandra DeLaney, Sean P Spencer, Anthony T Virtue, EnJun Yang, Alejandro Villarino, Makoto Kurachi, Margaret C Dunagin, Gretchen Harms Pritchard, Judith Stein, Cynthia Hughes, Diogo Fonseca-Pereira, Henrique Veiga-Fernandes, Arjun Raj, Taku Kambayashi, Igor E Brodsky, John J O'Shea, E John Wherry, Loyal A Goff, John L Rinn, Adam Williams, Richard A Flavell, Jorge Henao-Mejia
Commitment to the innate lymphoid cell (ILC) lineage is determined by Id2, a transcriptional regulator that antagonizes T and B cell-specific gene expression programs. Yet how Id2 expression is regulated in each ILC subset remains poorly understood. We identified a cis-regulatory element demarcated by a long non-coding RNA (lncRNA) that controls the function and lineage identity of group 1 ILCs, while being dispensable for early ILC development and homeostasis of ILC2s and ILC3s. The locus encoding this lncRNA, which we termed Rroid, directly interacted with the promoter of its neighboring gene, Id2, in group 1 ILCs...
September 19, 2017: Immunity
M Joaquina Delás, Leah R Sabin, Egor Dolzhenko, Simon Rv Knott, Ester Munera Maravilla, Benjamin T Jackson, Sophia A Wild, Tatjana Kovacevic, Eva Maria Stork, Meng Zhou, Nicolas Erard, Emily Lee, David R Kelley, Mareike Roth, Ine S Am Barbosa, Johannes Zuber, John L Rinn, Andrew D Smith, Gregory J Hannon
A substantial fraction of the genome is transcribed in a cell-type-specific manner, producing long non-coding RNAs (lncRNAs), rather than protein-coding transcripts. Here, we systematically characterize transcriptional dynamics during hematopoiesis and in hematological malignancies. Our analysis of annotated and de novo assembled lncRNAs showed many are regulated during differentiation and mis-regulated in disease. We assessed lncRNA function via an in vivo RNAi screen in a model of acute myeloid leukemia. This identified several lncRNAs essential for leukemia maintenance, and found that a number act by promoting leukemia stem cell signatures...
September 6, 2017: ELife
Stephano S Mello, Carolyn Sinow, Nitin Raj, Pawel K Mazur, Kathryn Bieging-Rolett, Daniela Kenzelmann Broz, Jamie F Conklin Imam, Hannes Vogel, Laura D Wood, Julien Sage, Tetsuro Hirose, Shinichi Nakagawa, John Rinn, Laura D Attardi
The p53 gene is mutated in over half of all cancers, reflecting its critical role as a tumor suppressor. Although p53 is a transcriptional activator that induces myriad target genes, those p53-inducible genes most critical for tumor suppression remain elusive. Here, we leveraged p53 ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) and RNA-seq (RNA sequencing) data sets to identify new p53 target genes, focusing on the noncoding genome. We identify Neat1 , a noncoding RNA (ncRNA) constituent of paraspeckles, as a p53 target gene broadly induced by mouse and human p53 in different cell types and by diverse stress signals...
June 1, 2017: Genes & Development
Yaara Zwang, Oliver Jonas, Casandra Chen, Mikael L Rinne, John G Doench, Federica Piccioni, Li Tan, Hai-Tsang Huang, Jinhua Wang, Young Jin Ham, Joyce O'Connell, Patrick Bhola, Mihir Doshi, Matthew Whitman, Michael Cima, Anthony Letai, David E Root, Robert S Langer, Nathanael Gray, William C Hahn
Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition...
May 31, 2017: ELife
Iain John McGurgan, David Joseph Nicholl
No abstract text is available yet for this article.
August 2017: Practical Neurology
Marta Melé, Kaia Mattioli, William Mallard, David M Shechner, Chiara Gerhardinger, John L Rinn
While long intergenic noncoding RNAs (lincRNAs) and mRNAs share similar biogenesis pathways, these transcript classes differ in many regards. LincRNAs are less evolutionarily conserved, less abundant, and more tissue-specific, suggesting that their pre- and post-transcriptional regulation is different from that of mRNAs. Here, we perform an in-depth characterization of the features that contribute to lincRNA regulation in multiple human cell lines. We find that lincRNA promoters are depleted of transcription factor (TF) binding sites, yet enriched for some specific factors such as GATA and FOS relative to mRNA promoters...
January 2017: Genome Research
Whitney S Henry, David G Hendrickson, Francisco Beca, Benjamin Glass, Marianne Lindahl-Allen, Lizhi He, Zhe Ji, Kevin Struhl, Andrew H Beck, John L Rinn, Alex Toker
Long non-coding RNAs (lncRNAs) have been implicated in normal cellular homeostasis as well as pathophysiological conditions, including cancer. Here we performed global gene expression profiling of mammary epithelial cells transformed by oncogenic v-Src, and identified a large subset of uncharacterized lncRNAs potentially involved in breast cancer development. Specifically, our analysis revealed a novel lncRNA, LINC00520 that is upregulated upon ectopic expression of oncogenic v-Src, in a manner that is dependent on the transcription factor STAT3...
December 13, 2016: Oncotarget
Ignacio S Caballero, Anna N Honko, Stephen K Gire, Sarah M Winnicki, Marta Melé, Chiara Gerhardinger, Aaron E Lin, John L Rinn, Pardis C Sabeti, Lisa E Hensley, John H Connor
BACKGROUND: Ebola virus is the causative agent of a severe syndrome in humans with a fatality rate that can approach 90 %. During infection, the host immune response is thought to become dysregulated, but the mechanisms through which this happens are not entirely understood. In this study, we analyze RNA sequencing data to determine the host response to Ebola virus infection in circulating immune cells. RESULTS: Approximately half of the 100 genes with the strongest early increases in expression were interferon-stimulated genes, such as ISG15, OAS1, IFIT2, HERC5, MX1 and DHX58...
September 5, 2016: BMC Genomics
Jonathan J Kotzin, Sean P Spencer, Sam J McCright, Dinesh B Uthaya Kumar, Magalie A Collet, Walter K Mowel, Ellen N Elliott, Asli Uyar, Michelle A Makiya, Margaret C Dunagin, Christian C D Harman, Anthony T Virtue, Stella Zhu, Will Bailis, Judith Stein, Cynthia Hughes, Arjun Raj, E John Wherry, Loyal A Goff, Amy D Klion, John L Rinn, Adam Williams, Richard A Flavell, Jorge Henao-Mejia
Neutrophils, eosinophils and 'classical' monocytes collectively account for about 70% of human blood leukocytes and are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is critical to maintain protective immune responses and minimize the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here we identify a long non-coding RNA that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and classical monocytes in response to pro-survival cytokines in mice...
September 8, 2016: Nature
Abigail F Groff, Diana B Sanchez-Gomez, Marcela M L Soruco, Chiara Gerhardinger, A Rasim Barutcu, Eric Li, Lara Elcavage, Olivia Plana, Lluvia V Sanchez, James C Lee, Martin Sauvageau, John L Rinn
The Linc-p21 locus, encoding a long non-coding RNA, plays an important role in p53 signaling, cell-cycle regulation, and tumor suppression. However, despite extensive study, confusion exists regarding its mechanism of action: is activity driven by the transcript acting in trans, in cis, or by an underlying functional enhancer? Here, using a knockout mouse model and a massively parallel enhancer assay, we delineate the functional elements at this locus. We observe that, even in tissues with no detectable Linc-p21 transcript, deletion of the locus significantly affects local gene expression, including of the cell-cycle regulator Cdkn1a...
August 23, 2016: Cell Reports
Marta Melé, John L Rinn
There is growing evidence that transcription and nuclear organization are tightly linked. Yet, whether transcription of thousands of long noncoding RNAs (lncRNAs) could play a role in this packaging process remains elusive. Although some lncRNAs have been found to have clear roles in nuclear architecture (e.g., FIRRE, NEAT1, XIST, and others), the vast majority remain poorly understood. In this Perspective, we highlight how the act of transcription can affect nuclear architecture. We synthesize several recent findings into a proposed model where the transcription of lncRNAs can serve as guide-posts for shaping genome organization...
June 2, 2016: Molecular Cell
David R Kelley, Jasper Snoek, John L Rinn
The complex language of eukaryotic gene expression remains incompletely understood. Despite the importance suggested by many noncoding variants statistically associated with human disease, nearly all such variants have unknown mechanisms. Here, we address this challenge using an approach based on a recent machine learning advance-deep convolutional neural networks (CNNs). We introduce the open source package Basset to apply CNNs to learn the functional activity of DNA sequences from genomics data. We trained Basset on a compendium of accessible genomic sites mapped in 164 cell types by DNase-seq, and demonstrate greater predictive accuracy than previous methods...
July 2016: Genome Research
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