Positional distribution of human transcription factor binding sites

TL;DR

This study introduces a method to analyze the positional distribution of human transcription factor binding sites using ChIP-chip data, revealing a common bimodal pattern near TSS and associating binding patterns with biological functions.

Contribution

The paper presents a novel approach for estimating TF binding site distributions and applies it to nine TFs, uncovering a shared bimodal distribution pattern and functional associations.

Findings

Binding sites are concentrated within 300 bp upstream of TSS

Distribution of binding sites shows a bimodal pattern

Target genes are linked to specific biological processes

Abstract

We developed a method for estimating the positional distribution of transcription fac-tor (TF) binding sites using ChIP-chip data, and applied it to recently published experiments on binding sites of nine TFs; OCT4, SOX2, NANOG, HNF1A, HNF4A, HNF6, FOXA2, USF1 and CREB1. The data were obtained from a genome-wide cov-erage of promoter regions from 8kb upstream of the Transcription Start Site (TSS) to 2kb downstream. The number of target genes of each TF ranges from few hundred to several thousand. We found that for each of the nine TFs the estimated binding site distribution is closely approximated by a mixture of two components: a narrow peak, localized within 300 base pairs upstream of the TSS, and a distribution of almost uni-form density within the tested region. Using Gene Ontology and Enrichment analysis, we were able to associate (for each of the TFs studied) the target genes of both types of binding with known biological processes. Most GO terms were enriched either among the proximal targets or among those with a uniform distribution of binding sites. For example, the three stemness-related TFs have several hundred target genes that belong to "development" and "morphogenesis" whose binding sites belong to the uniform dis-tribution.