Predicting expression: the complementary power of histone modification and transcription factor binding data.

David M Budden,Melissa J Davis,John F Markham,Daniel G Hurley,Edmund J Crampin,Joseph Cursons

doi:10.1186/1756-8935-7-36

Abstract

BackgroundTranscription factors (TFs) and histone modifications (HMs) play critical roles in gene expression by regulating mRNA transcription. Modelling frameworks have been developed to integrate high-throughput omics data, with the aim of elucidating the regulatory logic that results from the interactions of DNA, TFs and HMs. These models have yielded an unexpected and poorly understood result: that TFs and HMs are statistically redundant in explaining mRNA transcript abundance at a genome-wide level.ResultsWe constructed predictive models of gene expression by integrating RNA-sequencing, TF and HM chromatin immunoprecipitation sequencing and DNase I hypersensitivity data for two mammalian cell types. All models identified genome-wide statistical redundancy both within and between TFs and HMs, as previously reported. To investigate potential explanations, groups of genes were constructed for ontology-classified biological processes. Predictive models were constructed for each process to explore the distribution of statistical redundancy. We found significant variation in the predictive capacity of TFs and HMs across these processes and demonstrated the predictive power of HMs to be inversely proportional to process enrichment for housekeeping genes.ConclusionsIt is well established that the roles played by TFs and HMs are not functionally redundant. Instead, we attribute the statistical redundancy reported in this and previous genome-wide modelling studies to the heterogeneous distribution of HMs across chromatin domains. Furthermore, we conclude that statistical redundancy between individual TFs can be readily explained by nucleosome-mediated cooperative binding. This could possibly help the cell confer regulatory robustness by rejecting signalling noise and allowing control via multiple pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/1756-8935-7-36) contains supplementary material, which is available to authorized users.

Highlights

Transcription factors (TFs) and histone modifications (HMs) play critical roles in gene expression by regulating mRNA transcription
Transcription factors and histone modifications are predictive of mRNA transcript abundance As TFs and HMs are known to play critical roles in regulating transcription, accurate predictive models of mRNA transcript abundance have been constructed from corresponding chromatin immunoprecipitation (ChIP)-seq binding data for various organisms, cell types and modelling techniques [14,17,18,19]
Transcription factors and histone modifications provide equivalent information regarding genome-wide transcriptional regulation In Table 1, we present the prediction accuracy of loglinear and support vector regression (SVR) models constructed from three sets of data: TF binding (TF), HM and DNase-I hypersensitivity (HM+DNase) and the concatenation of both (TF+HM+DNase)

Summary

Introduction

Transcription factors (TFs) and histone modifications (HMs) play critical roles in gene expression by regulating mRNA transcription. Significant regulation is known to occur at the level of transcriptional initiation and elongation [1], through the combinatorial interactions of transcription factors (TFs) [2,3] and histone modifications (HMs) [4,5]. Direct interactions between TFs and the transcription pre-initiation complex require genomic proximity to the transcription start site (TSS) or higher-order chromatin looping [6], corresponding with TF-binding motifs in the promoter or enhancer/silencer regions respectively [2,7]. Post-translational modifications of the amino-termini of nucleosomal histones are known to regulate transcription [8,9] by either modulating the local chromatin structure to control TF accessibility [4] or directly recruiting chromatin remodellers and other related enzymes [10]. Altered gene expression caused by abnormalities in TF or HM patterns has been directly associated with hundreds of human diseases [3], including leukaemia [11], prostate cancer [12] and various developmental, autoimmune, neurological, inflammatory and neoplastic disorders [13]

Methods

Results

Conclusion