• ES Wong, BM Schmitt, A Kazachenka, D Thybert, A Redmond, F Connor, TF Rayner, C Feig, AC Ferguson-Smith, JC Marioni, DT Odom, P Flicek. Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution. Nat Commun 2017;8(1):1092. doi:10.1038/s41467-017-01037-x
  [BibTeX] [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.

  @Article{29061983,
  author = {Wong ES and Schmitt BM and Kazachenka A and Thybert D and Redmond A and Connor F and Rayner TF and Feig C and Ferguson-Smith AC and Marioni JC and Odom DT and Flicek P},
  title = {Interplay of cis and trans mechanisms driving transcription factor binding and gene expression evolution},
  journal = {Nat Commun},
  volume = {8},
  number = {1},
  pages = {1092},
  year = {2017},
  doi = {10.1038/s41467-017-01037-x},
  note = {First posted as a preprint: 19 June 2016},
  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.},}

Description 

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.

Full details have been published in  Nature Communications  .

Raw Data

The raw ChIP-seq data for can be found in ArrayExpress with the accession number  E-MTAB-4089.

Processed Data

Processed data is available for FOXA1, CEBFA, HNF4A and H3K4me3 as a binary format Excel workbook (xlsb) linked  here .  Column headings for the data spreadsheets are:

chr_position	Location of SNV underlying TFBS
suffix of .b	Normalized counts for BL6 F0 individuals
suffix of .c	Normalized counts for CAST F0 individuals
r	Dispersion estimate
suffix of .bi	Counts for BL6 allele in BL6xCAST individuals – where total counts (sum of allelic counts) have been adjusted for sequencing depth disparities across F1 libraries
suffix of .br	Counts for BL6 allele in CASTxBL6 individuals –  where total counts (sum of allelic counts) have been adjusted for sequencing depth disparities across F1 libraries
suffix of .ci	Counts for CAST allele in BL6xCAST individuals –  where total counts (sum of allelic counts) have been adjusted for sequencing depth disparities across F1 libraries
suffix of .cr	Counts for CAST allele in CASTxBL6 individuals –  where total counts (sum of allelic counts) have been adjusted for sequencing depth disparities across F1 libraries
cons likelihood	Llikelihood of data fitting the cons model
cis likelihood	Likelihood of data fitting the cis model
trans likelihood	Likelihood of data fitting the trans model
cistrans likelihood	Llikelihood of data fitting the cistrans model
cons_bic	BIC for cons
cis_bic	BIC for cis
trans_bic	BIC for trans
cistrans_bic	BIC for cistrans
cat	Category with lowest BIC

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