Variation in transcription factor binding among humans - PubMed (original) (raw)

Comparative Study

. 2010 Apr 9;328(5975):232-5.

doi: 10.1126/science.1183621. Epub 2010 Mar 18.

Fabian Grubert, Christopher Heffelfinger, Manoj Hariharan, Akwasi Asabere, Sebastian M Waszak, Lukas Habegger, Joel Rozowsky, Minyi Shi, Alexander E Urban, Mi-Young Hong, Konrad J Karczewski, Wolfgang Huber, Sherman M Weissman, Mark B Gerstein, Jan O Korbel, Michael Snyder

Affiliations

Comparative Study

Variation in transcription factor binding among humans

Maya Kasowski et al. Science. 2010.

Abstract

Differences in gene expression may play a major role in speciation and phenotypic diversity. We examined genome-wide differences in transcription factor (TF) binding in several humans and a single chimpanzee by using chromatin immunoprecipitation followed by sequencing. The binding sites of RNA polymerase II (PolII) and a key regulator of immune responses, nuclear factor kappaB (p65), were mapped in 10 lymphoblastoid cell lines, and 25 and 7.5% of the respective binding regions were found to differ between individuals. Binding differences were frequently associated with single-nucleotide polymorphisms and genomic structural variants, and these differences were often correlated with differences in gene expression, suggesting functional consequences of binding variation. Furthermore, comparing PolII binding between humans and chimpanzee suggests extensive divergence in TF binding. Our results indicate that many differences in individuals and species occur at the level of TF binding, and they provide insight into the genetic events responsible for these differences.

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Figures

Fig. 1

Fig. 1

Effect of SNPs on NFκB and PolII binding. (A) Signal tracks of a NFκB motif and a TATA-box demonstrate effects of B-SNPs on TF binding, with correlations in the expected direction (i.e., with “correct trend”). (B) Fold enrichments for cumulative SNP-differences affecting BRs and for single SNPs affecting motifs, in pair-wise comparisons between individuals relative to the overall frequency of binding differences for NFκB (7.5%) and PolII (25%). (C) B-SNPs affecting motifs frequently lead to binding differences with “correct trend”. *P<0.001, based on randomization tests involving 10,000 permutations, i.e. permutation tests). (D) BRs adjacent to differentially bound BRs are enriched for binding variation.

Fig. 2

Fig. 2

Effect of SVs on TF binding. (A) Example of a deletion affecting PolII binding. This example also shows a comparison of PolII occupancy in humans and a chimpanzee. A subset of individuals shares the chimpanzee binding phenotype. (B) Effect-sizes for microarray-based CNVs, SV-DELs (deletions identified by paired-end mapping), and SV-INVs (inversions detected by paired-end mapping). (C) Binding differences in regions displaying CNVs and SV-DELs frequently follow the “correct trend” in pair-wise comparisons between individuals. *P<0.01, based on permutation tests.

Fig. 3

Fig. 3

Correlation and effect sizes of TF binding and gene expression. (A) Example showing a correlation of binding and expression. This figure also shows a transgression event, in which the daughter displays a strong increase in binding relative to the parents. Continuous signal tracks shown in Fig. S10C. (B) Regions with binding variation correlate with differences in expression. Dark blue dots: PolII BRs displaying significant differences in binding in pair-wise comparisons between individuals; light blue dots: other BRs. The black lines demarcate data points that either fall two standard deviations outside the binding ratio or gene expression distributions. Indicated counts represent data points falling into the four corners for each data set. (C) Strong correlation between binding and gene expression at BRs in which a B-SNP intersects with the PolII specific CAAT-box. (D) Breakdown of segregation events in the trio showing the extent of BRs with candidate transgression events.

Fig. 4

Fig. 4

Comparison of PolII binding in humans and a chimpanzee. (A) Signal tracks for a peak found only in the chimpanzee. All ten individuals shown in Fig. S11B. B) Pie charts displaying occupancy by PolII of genomic regions where the chimp and human genomes are in synteny.

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