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

Verena M. Link, Sascha H. Duttke, Hyun B. Chun, Inge R. Holtman, Emma Westin, Marten A. Hoeksema, Yohei Abe, Dylan Skola, Casey E. Romanoski, Jenhan Tao, Gregory J. Fonseca, Ty D. Troutman, Nathanael J. Spann, Tobias Strid, Mashito Sakai, Miao Yu, Rong Hu, Rongxin Fang, Dirk Metzler, Bing RenChristopher K. Glass*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

48 Citations (Scopus)

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 similar to 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.

Original languageEnglish
Pages (from-to)1796-1809.e17
Number of pages31
JournalCell
Volume173
Issue number7
DOIs
Publication statusPublished - 14-Jun-2018

Keywords

  • CHROMATIN INTERACTIONS
  • GENE-EXPRESSION
  • HUMAN PROMOTERS
  • READ ALIGNMENT
  • HUMAN GENOME
  • ENHANCERS
  • SELECTION
  • SEQ
  • CONSERVATION
  • ENVIRONMENT

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