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

Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. We measured allele-specific TF binding affinity of three liver-specific TFs between crosses of two inbred mouse strains to elucidate the regulatory mechanisms underlying transcription factor (TF) binding variations in mammals. Our results highlight the preeminence of cis-acting variants on TF occupancy divergence. TF 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 TF 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 TF occupancy, chromatin state, and gene expression in complex mammalian cell states.