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dc.contributor.advisorEric S. Lander.en_US
dc.contributor.authorEngreitz, Jesse M. (Jesse Michael)en_US
dc.contributor.otherHarvard--MIT Program in Health Sciences and Technology.en_US
dc.date.accessioned2016-09-30T19:38:34Z
dc.date.available2016-09-30T19:38:34Z
dc.date.copyright2016en_US
dc.date.issued2016en_US
dc.identifier.urihttp://hdl.handle.net/1721.1/104616
dc.descriptionThesis: Ph. D. in Bioinformatics and Integrative Genomics, Harvard-MIT Program in Health Sciences and Technology, 2016.en_US
dc.descriptionCataloged from PDF version of thesis.en_US
dc.descriptionIncludes bibliographical references.en_US
dc.description.abstractOur genomes encode the molecular information that gives rise to life, yet we are just beginning to unravel how this information is organized, interpreted, and regulated. While the human genome contains -20,000 protein-coding genes, mammalian genomes also produce thousands of long non-coding RNAs (lncRNAs), some of which are now known to play essential roles in diverse biological processes including cellular differentiation and human disease. Recent studies show that many lncRNAs localize to the nucleus and interact with chromatin regulatory complexes, suggesting that some lncRNAs may represent a crucial missing component in our understanding of genome regulation. To test whether lncRNAs localize to and regulate specific sites in the genome, we developed genome-wide approaches to map lncRNA interactions with chromatin. Through studies of three conserved lncRNAs, we demonstrate that lncRNAs can exploit the three-dimensional architecture of the genome to identify their regulatory targets and, in turn, actively manipulate genome architecture to form subcompartments containing co-regulated genes. Thus, lncRNAs have unique capabilities as dynamic regulators that can locally amplify epigenetic signals. We next explored whether this model might apply to other long noncoding RNAs, many of which are not conserved across species and thus whose functions remain unclear. Through genetic dissection of their local regulatory functions, we show that many of these genomic loci participate in the local regulation of gene expression, but that these functions do not involve the IncRNA transcripts themselves. Instead, multiple mechanisms associated with RNA production including their promoters, the process of transcription, and RNA splicing - act in local networks of regulatory connections between spatially proximal genes, both protein-coding and noncoding. These findings reveal novel mechanistic explanations for the functions and evolution of noncoding transcription in mammalian genomes. Together these studies suggest a model in which mammalian gene regulation is organized into local neighborhoods defined by the spatial architecture of the genome. Within these neighborhoods, lncRNAs and DNA regulatory elements may function cooperatively to coordinate local gene expression. Dissecting this fundamental model for genome regulation may enable manipulation of the processes that interpret our genome sequence and galvanize efforts to develop new treatments for human disease.en_US
dc.description.statementofresponsibilityby Jesse M. Engreitz.en_US
dc.format.extent313 pagesen_US
dc.language.isoengen_US
dc.publisherMassachusetts Institute of Technologyen_US
dc.rightsM.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.en_US
dc.rights.urihttp://dspace.mit.edu/handle/1721.1/7582en_US
dc.subjectHarvard--MIT Program in Health Sciences and Technology.en_US
dc.titleGenome regulation by long noncoding RNAsen_US
dc.title.alternativeGenome regulation by lncRNAsen_US
dc.title.alternativeGenome regulation by long noncoding Ribonucleic acidsen_US
dc.typeThesisen_US
dc.description.degreePh. D. in Bioinformatics and Integrative Genomicsen_US
dc.contributor.departmentHarvard--MIT Program in Health Sciences and Technology.en_US
dc.identifier.oclc959009677en_US


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