Predicting gene expression in T cell differentiation from histone modifications and transcription factor binding affinities by linear mixture models

Ivan G Costa,Thais G Do Rego,Francisco De At De Carvalho,Helge G Roider

doi:10.1186/1471-2105-12-s1-s29

Abstract

BackgroundThe differentiation process from stem cells to fully differentiated cell types is controlled by the interplay of chromatin modifications and transcription factor activity. Histone modifications or transcription factors frequently act in a multi-functional manner, with a given DNA motif or histone modification conveying both transcriptional repression and activation depending on its location in the promoter and other regulatory signals surrounding it.ResultsTo account for the possible multi functionality of regulatory signals, we model the observed gene expression patterns by a mixture of linear regression models. We apply the approach to identify the underlying histone modifications and transcription factors guiding gene expression of differentiated CD4+ T cells. The method improves the gene expression prediction in relation to the use of a single linear model, as often used by previous approaches. Moreover, it recovered the known role of the modifications H3K4me3 and H3K27me3 in activating cell specific genes and of some transcription factors related to CD4+ T differentiation.

Highlights

The differentiation process from stem cells to fully differentiated cell types is controlled by the interplay of chromatin modifications and transcription factor activity
As a first step we supply our algorithm with a matrix X containing only predicted transcription factors (TFs) binding affinities, only histone modification data or both sets of regulatory signals and assess how well the resulting regression models can capture the data
The model selection procedure indicates that the data is optimally explained by the combination of 2-4 regression models and that gene expression data can be well predicted based on histone modification data alone

Summary

Introduction

The differentiation process from stem cells to fully differentiated cell types is controlled by the interplay of chromatin modifications and transcription factor activity. In response to different infectious agents Naive CD4+ T cells differentiate into at least four types of T helper cells—Th1, Th2, Th17, and inducible regulatory T cells (iTregs) [1]. While all of these cell types are involved in the adaptive immune response they serve distinct roles by secreting different cytokines. The differentiation process from stem cells to fully differentiated cell types is controlled by the interplay of chromatin modifications and transcription factor activity [2]. The affinity of histones to DNA is modified by the cell via a large repertoire of post-translational protein modifications including acetylations and methylations

Methods

Results

Conclusion