Asymmetric Conservation within Pairs of Co-Occurred Motifs Mediates Weak Direct Binding of Transcription Factors in ChIP-Seq Data.

Victor Levitsky,Tatyana Merkulova,Dmitry Oshchepkov,Elena Zemlyanskaya

doi:10.3390/ijms21176023

Abstract

(1) Background: Transcription factors (TFs) are main regulators of eukaryotic gene expression. The cooperative binding to genomic DNA of at least two TFs is the widespread mechanism of transcription regulation. Cooperating TFs can be revealed through the analysis of co-occurrence of their motifs. (2) Methods: We applied the motifs co-occurrence tool (MCOT) that predicted pairs of spaced or overlapped motifs (composite elements, CEs) for a single ChIP-seq dataset. We improved MCOT capability for the prediction of asymmetric CEs with one of the participating motifs possessing higher conservation than another does. (3) Results: Analysis of 119 ChIP-seq datasets for 45 human TFs revealed that almost for all families of TFs the co-occurrence with an overlap between motifs of target TFs and more conserved partner motifs was significantly higher than that for less conserved partner motifs. The asymmetry toward partner TFs was the most clear for partner motifs of TFs from the ETS (E26 Transformation Specific) family. (4) Conclusion: Co-occurrence with an overlap of less conserved motif of a target TF and more conserved motifs of partner TFs explained a substantial portion of ChIP-seq data lacking conserved motifs of target TFs. Among other TF families, conservative motifs of TFs from ETS family were the most prone to mediate interaction of target TFs with its weak motifs in ChIP-seq.

Highlights

Tissue, cell- and stage-specific regulation of gene expression is produced through interactions of transcription factors (TFs) with respective regulatory elements called binding sites (BSs) or motifs; typically, each TF functions in tight cooperation with other TFs: there is a variety of mechanisms for cooperative TF–DNA binding [1,2]
Many studies confirmed that ChIP-seq data possessed a substantial portion of binding regions lacking the conserved motifs of target TFs [12,19]
We improved the previous algorithm [11] for estimation of the significance of such asymmetric composite elements (CEs) (Figure 1C, Table 1) and developed the novel methodology to measure the asymmetry within CEs toward one of the participant motifs (Table 2)

Summary

Introduction

Tissue-, cell- and stage-specific regulation of gene expression is produced through interactions of transcription factors (TFs) with respective regulatory elements called binding sites (BSs) or motifs; typically, each TF functions in tight cooperation with other TFs: there is a variety of mechanisms for cooperative TF–DNA binding [1,2]. These mechanisms may be classified into simultaneous and sequential [1].

Objectives

Results

Conclusion