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Effects of sequence variation on differential allelic transcription factor occupancy and gene expression.

Publication ,  Journal Article
Reddy, TE; Gertz, J; Pauli, F; Kucera, KS; Varley, KE; Newberry, KM; Marinov, GK; Mortazavi, A; Williams, BA; Song, L; Crawford, GE; Wold, B ...
Published in: Genome Res
May 2012

A complex interplay between transcription factors (TFs) and the genome regulates transcription. However, connecting variation in genome sequence with variation in TF binding and gene expression is challenging due to environmental differences between individuals and cell types. To address this problem, we measured genome-wide differential allelic occupancy of 24 TFs and EP300 in a human lymphoblastoid cell line GM12878. Overall, 5% of human TF binding sites have an allelic imbalance in occupancy. At many sites, TFs clustered in TF-binding hubs on the same homolog in especially open chromatin. While genetic variation in core TF binding motifs generally resulted in large allelic differences in TF occupancy, most allelic differences in occupancy were subtle and associated with disruption of weak or noncanonical motifs. We also measured genome-wide differential allelic expression of genes with and without heterozygous exonic variants in the same cells. We found that genes with differential allelic expression were overall less expressed both in GM12878 cells and in unrelated human cell lines. Comparing TF occupancy with expression, we found strong association between allelic occupancy and expression within 100 bp of transcription start sites (TSSs), and weak association up to 100 kb from TSSs. Sites of differential allelic occupancy were significantly enriched for variants associated with disease, particularly autoimmune disease, suggesting that allelic differences in TF occupancy give functional insights into intergenic variants associated with disease. Our results have the potential to increase the power and interpretability of association studies by targeting functional intergenic variants in addition to protein coding sequences.

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Published In

Genome Res

DOI

EISSN

1549-5469

Publication Date

May 2012

Volume

22

Issue

5

Start / End Page

860 / 869

Location

United States

Related Subject Headings

  • Transcription Factors
  • Sequence Analysis, RNA
  • Regulatory Elements, Transcriptional
  • RNA Polymerase II
  • Protein Binding
  • Polymorphism, Single Nucleotide
  • Introns
  • Humans
  • Genome, Human
  • Genetic Variation
 

Citation

APA
Chicago
ICMJE
MLA
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Reddy, T. E., Gertz, J., Pauli, F., Kucera, K. S., Varley, K. E., Newberry, K. M., … Myers, R. M. (2012). Effects of sequence variation on differential allelic transcription factor occupancy and gene expression. Genome Research, 22(5), 860–869. https://doi.org/10.1101/gr.131201.111
Reddy, Timothy E., Jason Gertz, Florencia Pauli, Katerina S. Kucera, Katherine E. Varley, Kimberly M. Newberry, Georgi K. Marinov, et al. “Effects of sequence variation on differential allelic transcription factor occupancy and gene expression.Genome Research 22, no. 5 (May 2012): 860–69. https://doi.org/10.1101/gr.131201.111.
Reddy TE, Gertz J, Pauli F, Kucera KS, Varley KE, Newberry KM, et al. Effects of sequence variation on differential allelic transcription factor occupancy and gene expression. Genome research. 2012 May;22(5):860–9.
Reddy, Timothy E., et al. “Effects of sequence variation on differential allelic transcription factor occupancy and gene expression.Genome Research, vol. 22, no. 5, May 2012, pp. 860–69. Epmc, doi:10.1101/gr.131201.111.
Reddy TE, Gertz J, Pauli F, Kucera KS, Varley KE, Newberry KM, Marinov GK, Mortazavi A, Williams BA, Song L, Crawford GE, Wold B, Willard HF, Myers RM. Effects of sequence variation on differential allelic transcription factor occupancy and gene expression. Genome research. 2012 May;22(5):860–869.

Published In

Genome Res

DOI

EISSN

1549-5469

Publication Date

May 2012

Volume

22

Issue

5

Start / End Page

860 / 869

Location

United States

Related Subject Headings

  • Transcription Factors
  • Sequence Analysis, RNA
  • Regulatory Elements, Transcriptional
  • RNA Polymerase II
  • Protein Binding
  • Polymorphism, Single Nucleotide
  • Introns
  • Humans
  • Genome, Human
  • Genetic Variation