Transcription factor binding predicts histone modifications in human cell lines

Abstract

Gene expression in higher organisms is thought to be regulated by a complex network of transcription factor binding and chromatin modifications, yet the relative importance of these two factors remains a matter of debate. Here, we show that a computational approach allows surprisingly accurate prediction of histone modifications solely from knowledge of transcription factor binding both at promoters and at potential distal regulatory elements. This accuracy significantly and substantially exceeds what could be achieved by using DNA sequence as an input feature. Remarkably, we show that transcription factor binding enables strikingly accurate predictions across different cell lines. Analysis of the relative importance of specific transcription factors as predictors of specific histone marks recapitulated known interactions between transcription factors and histone modifiers. Our results demonstrate that reported associations between histone marks and gene expression may be indirect effects caused by interactions between transcription factors and histone-modifying complexes.epigenetics | gene regulation G ene expression is the fundamental process through which genetic information is dynamically and specifically deployed within cells. It is, therefore, of vital importance to all organisms and tightly controlled at both the transcriptional and posttranscriptional levels. Consequently, the elucidation of generegulatory mechanisms has been a central focus of biological research, with the area of transcriptional regulation having attracted intense attention over the last four decades.The canonical players in transcriptional regulation are sequence-specific DNA-binding transcription factors (TFs) that modulate gene expression by facilitating or inhibiting the recruitment of RNA polymerase to gene promoters (1). This paradigm has provided a powerful unifying mechanism for transcription, validated by a large amount of experimental evidence over the last five decades (see, e.g., ref. 2). Further evidence of the power of TFs to act as master regulators of gene expression and cell identity is illustrated by their ability to reprogram differentiated fibroblasts into embryonic stem (ES) cells (3).Research in the field of epigenetics has, however, suggested an alternative view that places posttranslational modifications of the histone subunits of nucleosomes in a central role of transcriptional regulation. The finding that particular combinations of histone modifications are associated with active and repressed gene promoters (4) has led to suggestions that a histone code controls gene expression (5, 6). Support for this hypothesis has come from the recent application of bioinformatic approaches to whole-genome measurements of both histone modifications and gene expression, which have demonstrated that gene expression can be predicted from histone modifications (7,8). This model has generated intense interest and is part of the stimulation behind the search for epigenetic causes of human disease (9).However, although histone mo...

Relationship between histone modifications and transcription factor binding is protein family specific

“…These studies reported increased performances in the sequence-based Cold Spring Harbor Laboratory Press on May 12, 2018 -Published by genome.cshlp.org Downloaded from modeling of in vivo TF binding events when such models incorporated HMs (Benveniste et al 2014;Liu et al 2015a). In this study, we described qualitatively and quantitatively the relationship between TF binding and HM patterns in a protein family-specific manner across different cell lines.…”

“…Recent studies reported a quantitative relationship between in vivo TF binding specificities and HM patterns surrounding BSs near DNA regulatory elements (Benveniste et al 2014;Liu et al 2015a). Given our qualitative observation that HM pattern preferences surrounding BSs are protein family-specific, an obvious question is whether HM patterns at TF BSs can add another layer to modeling genome-wide in vivo TF binding quantitatively in a protein family-specific manner.…”

“…For example, the GC content of a BS region can affect nucleosome positioning (Brogaard et al 2012). DNA shape features are derived from nucleotide sequences ), which are closely related to HM patterns (Henikoff and Shilatifard 2011;Benveniste et al 2014;Grubert et al 2015). With HM-augmented models that can increase the modeling accuracy of DNA binding specificities across TF families, we further separated the contributions from DNA sequence and shape at flanking regions and the contribution from HM patterns.…”

Transcription factor interaction with COMPASS-like complex regulates histone H3K4 trimethylation for specific gene expression in plants

“…Recently, computational analysis combined with chromatin immunoprecipitation followed by sequencing (ChIP-Seq) revealed that transcription factor binding predicts histone modifications in human cell lines (43), but the role of transcription factor in histone modifications over specific gene promoters has not been experimentally demonstrated. Our data showed that sequencespecific transcription factor regulates gene expression not only by recognizing specific DNA sequences, but also by facilitating histone modifications such as H3K4me3 at specific DNA sites through interaction with the COMPASS-like components Ash2 and WDR5a (Fig.…”

DGW: an exploratory data analysis tool for clustering and visualisation of epigenomic marks

“…Bieberstein and colleagues showed intriguing patterns of accumulation of the histone marks H3K4me3 and H3K9ac at splice sites [5], hinting at an architectural origin of the shape of the marks. More recently, Benveniste et al showed that histone marks can be very well predicted genome-wide by the binding patterns of transcription factors (TFs) [6]. The shape of the peak may therefore be a readout of additional chromatin-related events and genomic regions which are similarly marked may therefore hint at common regulatory or architectural features.…”