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

Abstract

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.

Evidence for multiple roles for grainyhead-like 2 in the establishment and maintenance of human mucociliary airway epithelium

“…ChIP-seq for GRHL2 was performed on HBE cells from three donors as described (40,41) (see also SI Materials and Methods; Gene Expression Omnibus accession no. GSE46194).…”

Patterns of regulatory activity across diverse human cell types predict tissue identity, transcription factor binding, and long-range interactions

“…This cluster (488) consists of 30 DHSs on the X chromosome that fall primarily into three loci, one of which surrounds the XIST gene. The second locus includes a noncoding RNA (LOC286467) recently shown to be the only locus on the X chromosome, besides XIST, with sex-specific Pol2 binding (Reddy et al 2012). The third locus also includes a poorly documented noncoding RNA (LOC550643).…”

Human active X-specific DNA methylation events showing stability across time and tissues

“…Another two regions, covering LOC286467 and near LOC642776, showed overlap between Xa probes and H3K4me3, both with an absence of gene expression differences (Supplementary Figures 5B and C). Remarkably, LOC286467 was previously identified as the only locus besides XIST with sex-specific RNA polymerase 2 binding, 33 and along with XIST, LOC550643 was the only locus with sex-specific DNAse I hypersensitivity patterns. 34 Unfortunately, the Infinium HM450 array did not cover the gene body of LOC550643, which showed H3K4me3 enrichment in females from the BLUEPRINT data.…”