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Goff, Loyal

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Goff

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Loyal

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Goff, Loyal
Author's Publications: search.filters.isAuthorOfPublication.cc0e355e-5377-4151-9349-e60042cc1d6a

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Now showing 1 - 7 of 7
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    DNMT1-interacting RNAs block gene specific DNA methylation
    (2013) Di Ruscio, Annalisa; Ebralidze, Alexander; Benoukraf, Touati; Amabile, Giovanni; Goff, Loyal; Terragni, Joylon; Figueroa, Maria Eugenia; De Figureido Pontes, Lorena Lobo; Alberich-Jorda, Meritxell; Zhang, Pu; Wu, Mengchu; D’Alò, Francesco; Melnick, Ari; Leone, Giuseppe; Ebralidze, Konstantin K.; Pradhan, Sriharsa; Rinn, John; Tenen, Daniel
    Summary DNA methylation was described almost a century ago. However, the rules governing its establishment and maintenance remain elusive. Here, we present data demonstrating that active transcription regulates levels of genomic methylation. We identified a novel RNA arising from the CEBPA gene locus critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extended the generality of this finding to numerous gene loci. Collectively, these results delineate the nature of DNMT1-RNA interactions and suggest strategies for gene selective demethylation of therapeutic targets in disease.
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    Multiple knockout mouse models reveal lincRNAs are required for life and brain development
    (eLife Sciences Publications, Ltd, 2013) Sauvageau, Martin; Goff, Loyal; Lodato, Simona; Bonev, Boyan; Groff, Abigail F.; Gerhardinger, Chiara; Sanchez-Gomez, Diana B; Hacisuleyman, Ezgi; Li, Eric; Spence, Matthew; Liapis, Stephen C; Mallard, William; Morse, Michael; Swerdel, Mavis R; D’Ecclessis, Michael F; Moore, Jennifer C; Lai, Venus; Gong, Guochun; Yancopoulos, George D; Frendewey, David; Kellis, Manolis; Hart, Ronald P; Valenzuela, David M; Arlotta, Paola; Rinn, John
    Many studies are uncovering functional roles for long noncoding RNAs (lncRNAs), yet few have been tested for in vivo relevance through genetic ablation in animal models. To investigate the functional relevance of lncRNAs in various physiological conditions, we have developed a collection of 18 lncRNA knockout strains in which the locus is maintained transcriptionally active. Initial characterization revealed peri- and postnatal lethal phenotypes in three mutant strains (Fendrr, Peril, and Mdgt), the latter two exhibiting incomplete penetrance and growth defects in survivors. We also report growth defects for two additional mutant strains (linc–Brn1b and linc–Pint). Further analysis revealed defects in lung, gastrointestinal tract, and heart in Fendrr−/− neonates, whereas linc–Brn1b−/− mutants displayed distinct abnormalities in the generation of upper layer II–IV neurons in the neocortex. This study demonstrates that lncRNAs play critical roles in vivo and provides a framework and impetus for future larger-scale functional investigation into the roles of lncRNA molecules. DOI: http://dx.doi.org/10.7554/eLife.01749.001
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    Long Noncoding RNAs Regulate Adipogenesis
    (Proceedings of the National Academy of Sciences, 2013) Sun, Lei; Goff, Loyal; Trapnell, Cole; Alexander, Ryan; Lo, Kinyui Alice; Hacisuleyman, Ezgi; Sauvageau, Martin; Tazon-Vega, Barbara; Kelley, David Roy; Hendrickson, David Gillis; Yuan, Bingbing; Kellis, Manolis; Lodish, Harvey F.; Rinn, John
    The prevalence of obesity has led to a surge of interest in understanding the detailed mechanisms underlying adipocyte development. Many protein-coding genes, mRNAs, and microRNAs have been implicated in adipocyte development, but the global expression patterns and functional contributions of long noncoding RNA (lncRNA) during adipogenesis have not been explored. Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, we have identified numerous lncRNAs that are functionally required for proper adipogenesis.
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    Topological Organization of Multi-chromosomal Regions by Firre
    (2014) Hacisuleyman, Ezgi; Goff, Loyal; Trapnell, Cole; Williams, Adam; Henao-Mejia, Jorge; Sun, Lei; McClanahan, Patrick; Hendrickson, David Gillis; Sauvageau, Martin; Kelley, David Roy; Morse, Michael; Engreitz, Jesse; Lander, Eric; Guttman, Mitch; Lodish, Harvey F.; Flavell, Richard; Raj, Arjun; Rinn, John
    RNA is known to be an abundant and important structural component of the nuclear matrix, including long noncoding RNAs (lncRNA). Yet the molecular identities, functional roles, and localization dynamics of lncRNAs that influence nuclear architecture remain poorly understood. Here, we describe one lncRNA, Firre, that interacts with the nuclear matrix factor hnRNPU, through a 156 bp repeating sequence and Firre localizes across a ~5 Mb domain on the X-chromosome. We further observed Firre localization across at least five distinct trans-chromosomal loci, which reside in spatial proximity to the Firre genomic locus on the X-chromosome. Both genetic deletion of the Firre locus or knockdown of hnRNPU resulted in loss of co-localization of these trans-chromosomal interacting loci. Thus, our data suggest a model in which lncRNAs such as Firre can interface with and modulate nuclear architecture across chromosomes.
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    Differential Gene and Transcript Expression Analysis of RNA-seq Experiments with TopHat and Cufflinks
    (Nature Publishing Group, 2012) Trapnell, Cole; Roberts, Adam; Goff, Loyal; Pertea, Geo; Kim, Daehwan; Kelley, David Roy; Pimentel, Harold; Salzberg, Steven L.; Rinn, John; Pachter, Lior
    Recent advances in high-throughput cDNA sequencing (RNA-seq) can reveal new genes and splice variants and quantify expression genome-wide in a single assay. The volume and complexity of data from RNA-seq experiments necessitate scalable, fast and mathematically principled analysis software. TopHat and Cufflinks are free, open-source software tools for gene discovery and comprehensive expression analysis of high-throughput mRNA sequencing (RNA-seq) data. Together, they allow biologists to identify new genes and new splice variants of known ones, as well as compare gene and transcript expression under two or more conditions. This protocol describes in detail how to use TopHat and Cufflinks to perform such analyses. It also covers several accessory tools and utilities that aid in managing data, including CummeRbund, a tool for visualizing RNA-seq analysis results. Although the procedure assumes basic informatics skills, these tools assume little to no background with RNA-seq analysis and are meant for novices and experts alike. The protocol begins with raw sequencing reads and produces a transcriptome assembly, lists of differentially expressed and regulated genes and transcripts, and publication-quality visualizations of analysis results. The protocol's execution time depends on the volume of transcriptome sequencing data and available computing resources but takes less than 1 d of computer time for typical experiments and ~1 h of hands-on time.
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    The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan
    (Springer Nature, 2016) Kotzin, Jonathan J.; Spencer, Sean Paul; McCright, Sam J.; Kumar, Dinesh B. Uthaya; Collet, Magalie A.; Mowel, Walter K.; Elliott, Ellen N.; Uyar, Asli; Makiya, Michelle A.; Dunagin, Margaret C.; Harman, Christian C.D.; Virtue, Anthony T.; Zhu, Stella; Bailis, Will; Stein, Judith; Hughes, Cynthia; Raj, Arjun; Wherry, E. John; Goff, Loyal; Klion, Amy D.; Rinn, John; Williams, Adam; Flavell, Richard A.; Henao-Mejia, Jorge
    Neutrophils, eosinophils and “classical” monocytes collectively account for ~70% ofhuman 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 while minimizing the deleterious consequences of prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely unknown. Here, we identify a novel long non-coding RNA (lncRNA) that we termed Morrbid, which tightly controls the survival of neutrophils, eosinophils and “classical” monocytes in response to pro-survival cytokines. To control the lifespan of these cells, Morrbid regulates the transcription of its neighboring pro-apoptotic gene, Bcl2l11 (Bim), by promoting the enrichment of the PRC2 complex at the Bcl2l11 promoter to maintain this gene in a poised state. Notably, Morrbid regulates this process in cis, enabling allelespecific control of Bcl2l11 transcription. Thus, in these highly inflammatory cells, changes in Morrbid levels provide a locus-specific regulatory mechanism that allows for rapid control of apoptosis in response to extracellular pro-survival signals. As MORRBID is present in humans and dysregulated in patients with hypereosinophilic syndrome, this lncRNA may represent a potential therapeutic target for inflammatory disorders characterized by aberrant short-lived myeloid cell lifespan.
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    RNase-mediated protein footprint sequencing reveals protein-binding sites throughout the human transcriptome
    (BioMed Central, 2014) Silverman, Ian M; Li, Fan; Alexander, Anissa; Goff, Loyal; Trapnell, Cole; Rinn, John; Gregory, Brian D
    Although numerous approaches have been developed to map RNA-binding sites of individual RNA-binding proteins (RBPs), few methods exist that allow assessment of global RBP–RNA interactions. Here, we describe PIP-seq, a universal, high-throughput, ribonuclease-mediated protein footprint sequencing approach that reveals RNA-protein interaction sites throughout a transcriptome of interest. We apply PIP-seq to the HeLa transcriptome and compare binding sites found using different cross-linkers and ribonucleases. From this analysis, we identify numerous putative RBP-binding motifs, reveal novel insights into co-binding by RBPs, and uncover a significant enrichment for disease-associated polymorphisms within RBP interaction sites.