CpG content-dependent associations between transcription factors and histone modifications.

Jonas Fischer,Jörn Walter,Fatemeh Behjati Ardakani,Kathrin Kattler,Marcel H Schulz,Roberto Mantovani

doi:10.1371/journal.pone.0249985

Jonas Fischer, Jörn Walter + Show 4 more

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https://doi.org/10.1371/journal.pone.0249985

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Abstract

Understanding the factors that underlie the epigenetic regulation of genes is crucial to understand the gene regulatory machinery as a whole. Several experimental and computational studies examined the relationship between different factors involved. Here we investigate the relationship between transcription factors (TFs) and histone modifications (HMs), based on ChIP-seq data in cell lines. As it was shown that gene regulation by TFs differs depending on the CpG class of a promoter, we study the impact of the CpG content in promoters on the associations between TFs and HMs. We suggest an approach based on sparse linear regression models to infer associations between TFs and HMs with respect to CpG content. A study of the partial correlation of HMs for the two classes of high and low CpG content reveals possible CpG dependence and potential candidates for confounding factors in our models. We show that the models are accurate, inferred associations reflect known biological relationships, and we give new insight into associations with respect to CpG content. Moreover, analysis of a ChIP-seq dataset in HepG2 cells of the HM H3K122ac, an HM about little is known, reveals novel TF associations and supports a previously established link to active transcription.

Highlights

Epigenetic modifications play a crucial role in the gene regulatory system
Starting with insights from this partial correlation, we present results that reveal CpG content dependence of regression model performance, promoter locality of transcription factors (TFs)–histone modifications (HMs) relationships, and show general relationships that reflect known interactions as well as potential new interaction partners
We discover hints for an association with activation when comparing the most significant TFs found for the different HMs in the HepG2 cell line, with similar TFs picked in H3K122ac and the marks H3K27ac and H3K4me3 associated with active genes (Table 1)

Summary

Introduction

Epigenetic modifications play a crucial role in the gene regulatory system. They allow a single DNA molecule to be interpreted in different cell types and throughout different developmental stages, by directly interacting with other regulatory factors or by reorganizing the DNA accessibility in the cell and thereby affecting gene transcription [1]. The genomic location of certain epigenetic modifications, the post-translational modifications of histone residues, can be measured by genome-wide assays such as chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) [2, 3]. Several consortia such as ENCODE [4, 5] and IHEC [6]. With this data at hand, epigenetics has the potential for a better understanding of, for instance, the cause and effect of diseases [7,8,9,10] and can lead to the development of novel therapeutic approaches for cancer [11, 12] or HIV [13]

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