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CROWDSOURCING: A NOVEL GROUP-LEVEL MECHANISM STRUCTURES CHROMATIN AND FOSTERS GENE-COMPLEX ACTIVATION

dc.contributor.advisorHannenhalli, Sridharen_US
dc.contributor.authorMalin, Justinen_US
dc.date.accessioned2016-02-06T06:45:35Z
dc.date.available2016-02-06T06:45:35Z
dc.date.issued2015en_US
dc.identifierhttps://doi.org/10.13016/M2C71V
dc.identifier.urihttp://hdl.handle.net/1903/17320
dc.description.abstractTranscriptional regulation of a co-expressed gene network often relies on adoption of a three-dimensional conformation, dubbed a ‘chromatin hub’ or ‘regulatory archipelago’, which radically reduces spatial distances between genomically remote enhancers and gene targets, as well as among enhancers. While the advantage of spatial proximity for fostering pairwise interactions is self-evident, there has been limited exploration within archipelagos of higher-order interactions. Here we probe the evidence for a novel and group-level mechanism which, we hypothesize, is emergent when numerous coordinately-acting regulatory enhancers, mediated by chromatin, converge in space. Based on functional human genomic data and biophysical modeling, and using a set of 40 enhancer archipelagos we identified through shared activity across 37 tissues, we show that three-dimensional juxtaposition of dozens of genomically dispersed binding sites for a given transcription factor (TF) can briefly ‘trap’ diffusing TF proteins, eliciting a spike in local TF concentration and a two-fold boost in its DNA occupancy at member enhancers. We find substantial evidence for the role of this ‘crowdsourcing’ effect in tissue-specific gene-complex activation, and in the process, offer the first evidence for a predictable group-level modulator of TF occupancy that operates independently of genomic distance. In turn, crowd-sourcing proves a surprising answer to the paradoxical source of binding specificity for degenerate TFs, in general, and various master regulator TFs, in particular. Additionally, we show that crowdsourcing likely contributes to super-enhancer functionality and speculate on crowdsourcing’s role in coordinating collectives of super-enhancers in cell lineage determination. Finally, we ask whether the biophysical impact of crowdsourcing also flows in the opposite direction. Here we find, likely mediated by elevated TF concentrations, that coordinately acting enhancers adopt a more compact conformation, stereotypical of activated gene complexes. Together, we find compelling evidence for a novel and pervasive regulatory mechanism that is emergent at the level of co-expressed gene module and which, both, mediates and is mediated by higher-order chromatin structure.en_US
dc.language.isoenen_US
dc.titleCROWDSOURCING: A NOVEL GROUP-LEVEL MECHANISM STRUCTURES CHROMATIN AND FOSTERS GENE-COMPLEX ACTIVATIONen_US
dc.typeDissertationen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.contributor.departmentBiologyen_US
dc.subject.pqcontrolledGeneticsen_US
dc.subject.pqcontrolledBiologyen_US
dc.subject.pquncontrolledarchipelagoen_US
dc.subject.pquncontrolledchromatin structureen_US
dc.subject.pquncontrolledcrowdsourcingen_US
dc.subject.pquncontrolledenhancersen_US
dc.subject.pquncontrolledtranscriptional regulationen_US
dc.subject.pquncontrolledtranscription factor bindingen_US


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