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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Bone Marrow Cells / cytology
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Cluster Analysis
  • Enhancer Elements, Genetic / genetics
  • Female
  • Gene Expression Regulation / drug effects
  • Genetic Variation*
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • CCAAT-Enhancer-Binding Protein-beta
  • CEBPB protein, human
  • Kdo2-lipid A
  • Lipopolysaccharides
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • proto-oncogene protein Spi-1