Friday, February 3, 2012

Fwd: Effects of sequence variation on differential allelic transcription factor occupancy and gene expression [RESEARCH]

.. variation on the theme (surely more to come!)
Fwd: please follow footer link
Effects of sequence variation on differential allelic transcription factor occupancy and gene expression [RESEARCH]:

A complex interplay between transcription factors (TFs) and the genome is essential for proper regulation of transcription. However, directly connecting variation in genomic DNA sequence with variation in TF binding and gene expression is challenging due to limited knowledge of where TFs bind and environmental differences between individuals and cell types. To address this problem, we measured genome-wide differential allelic occupancy of 24 sequence-specific TFs and EP300 in a human lymphoblastoid cell line (LCL), GM12878. Overall, 5% of human TF binding sites have an allelic imbalance in occupancy. At many sites, TFs were clustered together on the genome in TF-binding hubs, where they occupied the same homolog in regions of especially open chromatin. While genetic variation in core TF binding motifs generally resulted in large allelic differences in TF occupancy, the majority of allelic differences in occupancy were subtle and associated with disruption of weak or non-canonical DNA binding motifs. We also measured genome-wide differential allelic expression of genes both with and without heterozygous exonic variants in the same cells. We found that genes with differential allelic expression were overall less expressed, not just in GM12878 cells, but also in a panel of unrelated human cell lines. Comparing TF occupancy with expression, we found a strong association between allelic occupancy and expression within 100 bp of transcription start sites (TSSs), and a weak association up to 100 kb away from TSSs. When compared to disease-associated regions identified in genome-wide association studies, sites of differential allelic occupancy were significantly enriched for variants associated with disease, particularly autoimmune disease. These results highlight the potential for allelic differences in TF occupancy to 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.



(Original Post: Genome research (advanced).)