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Analysis of Genetically Diverse Macrophages Reveals Local and Domain-wide Mechanisms that Control Transcription Factor Binding and Function.
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA; Faculty of Biology, Division of Evolutionary Biology, Ludwig-Maximilian University of Munich, Munich, Germany.
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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2018 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 173, no 7, p. 1796-1809.e17, article id S0092-8674(18)30511-7Article in journal (Refereed) Published
Abstract [en]

Non-coding genetic variation is a major driver of phenotypic diversity and allows the investigation of mechanisms that control gene expression. Here, we systematically investigated the effects of >50 million variations from five strains of mice on mRNA, nascent transcription, transcription start sites, and transcription factor binding in resting and activated macrophages. We observed substantial differences associated with distinct molecular pathways. Evaluating genetic variation provided evidence for roles of ∼100 TFs in shaping lineage-determining factor binding. Unexpectedly, a substantial fraction of strain-specific factor binding could not be explained by local mutations. Integration of genomic features with chromatin interaction data provided evidence for hundreds of connected cis-regulatory domains associated with differences in transcription factor binding and gene expression. This system and the >250 datasets establish a substantial new resource for investigation of how genetic variation affects cellular phenotypes.

Place, publisher, year, edition, pages
Cambridge, United States: Cell Press , 2018. Vol. 173, no 7, p. 1796-1809.e17, article id S0092-8674(18)30511-7
Keywords [en]
chromatin structure, cis-regulatory domains, enhancer landscape, gene expression, genetic variation, macrophages, transcription factor binding
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-154607DOI: 10.1016/j.cell.2018.04.018ISI: 000437004000025PubMedID: 29779944Scopus ID: 2-s2.0-85046713531OAI: oai:DiVA.org:liu-154607DiVA, id: diva2:1290761
Available from: 2019-02-21 Created: 2019-02-21 Last updated: 2019-03-01Bibliographically approved

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