Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution

Nat Commun. 2017 Oct 23;8(1):1092. doi: 10.1038/s41467-017-01037-x.

Abstract

Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Here we measure allele-specific transcription factor binding occupancy of three liver-specific transcription factors between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor binding variations in mammals. Our results highlight the pre-eminence of cis-acting variants on transcription factor occupancy divergence. Transcription factor binding differences linked to cis-acting variants generally exhibit additive inheritance, while those linked to trans-acting variants are most often dominantly inherited. Cis-acting variants lead to local coordination of transcription factor occupancies that decay with distance; distal coordination is also observed and may be modulated by long-range chromatin contacts. Our results reveal the regulatory mechanisms that interplay to drive transcription factor occupancy, chromatin state, and gene expression in complex mammalian cell states.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Evolution, Molecular
  • Gene Expression Regulation, Fungal / genetics
  • Gene Expression Regulation, Fungal / physiology
  • Humans
  • Mice
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Chromatin
  • Transcription Factors