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

Emily S Wong,Christine Feig,Frances Connor,Tim F Rayner,Anastasiya Kazachenka,Anne C Ferguson-Smith,Aisling Redmond,David Thybert,Paul Flicek,Duncan T Odom,Bianca M Schmitt,John C Marioni

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.

Highlights

Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution
In order to dissect the extent of cis and trans variation in transcription factors (TFs) occupancy variation, transcription factor binding sites (TFBS) occupancy was mapped with six biological replicates using chromatin immunoprecipitation followed by sequencing (ChIP-seq) against three liver TFs (HNF4A, FOXA1, CEBPA) in inbred mouse subspecies C57BL/6J (BL6) and CAST/EiJ (CAST) and their F1 crosses (BL6xCAST and CASTxBL6) (Fig. 1a; Supplementary Figs. 1–3; Supplementary Tables 1, 2; “Methods”); all data are in ArrayExpress (E-MTAB-4089)
60–70,000 regions in the genome are bound by each TF (“Methods”), and ~20% had one or more single-nucleotide variants (SNVs) with sufficient sequencing coverage to permit quantitative allelic resolution of TF binding (Fig. 1b)

Summary

Introduction

Noncoding regulatory variants play a central role in the genetics of human diseases and in evolution. Cis-acting variants lead to local coordination of transcription factor occupancies that decay with distance; distal coordination is observed and may be modulated by long-range chromatin contacts. Cis-acting sequence changes substantially modulate TF occupancy[11, 12], but direct disruption of TF–DNA binding motifs is relatively rare[13,14,15,16,17,18,19]. This seemingly conflicting observation may be potentially explained by changes to surrounding chromatin state, long-range TF-TF connectivity[6], or cis-acting binding determinants near but outside the core binding motif[20]

Methods

Results

Conclusion