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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.

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