Dynamics of enhancers in myeloid antigen presenting cells upon LPS stimulation.

Alexis Vandenbon,Shunsuke Teraguchi,Daron M Standley,Osamu Takeuchi,Yutaka Suzuki

doi:10.1186/1471-2164-15-s10-s4

Alexis Vandenbon, Shunsuke Teraguchi + Show 3 more

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https://doi.org/10.1186/1471-2164-15-s10-s4

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Abstract

BackgroundRecent studies have underscored the role of enhancers in defining cell type-specific transcriptomes. Cell type-specific enhancers are bound by combinations of shared and cell type-specific transcription factors (TFs). However, little is known about combinatorial binding of TFs to enhancers, dynamics of TF binding following stimulation, or the downstream effects on gene expression. Here, we address these questions in two types of myeloid antigen presenting cells (APCs), macrophages and dendritic cells (DCs), before and after stimulation with lipopolysaccharide (LPS), a potent stimulator of the innate immune response.ResultsWe classified enhancers according to the combination of TFs binding them. There were significant correlations between the sets of TFs bound to enhancers prior to stimulation and expression changes of nearby genes after stimulation. Importantly, a set of enhancers pre-bound by PU.1, C/EBPβ, ATF3, IRF4, and JunB was strongly associated with induced genes and binding by stimulus-activated regulators. Our classification suggests that transient loss of ATF3 binding to a subset of these enhancers is important for regulation of early-induced genes. Changes in TF-enhancer binding after stimulation were correlated with binding by additional activated TFs and with the presence of proximally located enhancers.ConclusionsThe results presented in this study reveal the complexity and dynamics of TF- enhancer binding before and after stimulation in myeloid APCs.

Highlights

Recent studies have underscored the role of enhancers in defining cell type-specific transcriptomes
Identification of enhancer regions using epigenetic markers and transcription initiation events Given the known chromatin signature associated with active and inactive promoters and enhancer regions, we detected 165,446 genomic regions based on statistically significant enrichment of epigenetic markers, H3K4me3, H3K27me3, and H3K4me1 along with transcription initiation events
We initially classified enhancer regions according to the transcription factors (TFs) binding to them before stimulation, and we found a number of different enhancer classes, each defined by a different set of binding regulators

Summary

Introduction

Recent studies have underscored the role of enhancers in defining cell type-specific transcriptomes. Little is known about combinatorial binding of TFs to enhancers, dynamics of TF binding following stimulation, or the downstream effects on gene expression. We address these questions in two types of myeloid antigen presenting cells (APCs), macrophages and dendritic cells (DCs), before and after stimulation with lipopolysaccharide (LPS), a potent stimulator of the innate immune response. It is well established that enhancers play a key role in the regulation of gene expression [2,3]. Recent developments in sequencing techniques have enabled high-resolution investigation of a wide variety of histone modifications, and their functional annotation [4,5]. Enhancers have been shown to be marked by high amounts of the histone modification

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