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Cell. 2018 Jun 14;173(7):1796-1809.e17. doi: 10.1016/j.cell.2018.04.018. Epub 2018 May 17.

Analysis of Genetically Diverse Macrophages Reveals Local and Domain-wide Mechanisms that Control Transcription Factor Binding and Function.

Author information

1
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.
2
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
3
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.
4
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
5
Ludwig Institute for Cancer Research, La Jolla, CA, USA.
6
Faculty of Biology, Division of Evolutionary Biology, Ludwig-Maximilian University of Munich, Munich, Germany.
7
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA; Ludwig Institute for Cancer Research, La Jolla, CA, USA.
8
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA; Department of Medicine, University of California, San Diego, La Jolla, CA, USA. Electronic address: ckg@ucsd.edu.

Abstract

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.

KEYWORDS:

chromatin structure; cis-regulatory domains; enhancer landscape; gene expression; genetic variation; macrophages; transcription factor binding

PMID:
29779944
PMCID:
PMC6003872
[Available on 2019-06-14]
DOI:
10.1016/j.cell.2018.04.018

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