Abstract

T-cell activation induces context-specific gene expression programs that promote energy generation and biosynthesis, progression through the cell cycle and ultimately cell differentiation. The aim of this study was to apply the omni ATAC-seq method to characterize the landscape of chromatin changes induced by T-cell activation in mature naïve CD4+ T-cells. Using a well-established ex vivo protocol of canonical T-cell receptor signaling, we generated genome-wide chromatin maps of naïve T-cells from pediatric donors in quiescent or recently activated states. We identified thousands of individual chromatin accessibility peaks that are associated with T-cell activation, the majority of which were annotated intronic and intergenic enhancer regions. A core set of 3268 gene promoters underwent chromatin remodeling and concomitant changes in gene expression in response to activation, and were enriched in multiple pathways controlling cell cycle regulation, metabolism, inflammatory response genes and cell survival. Leukemia inhibitory factor (LIF) was among those factors that gained the highest accessibility and expression, in addition to IL2-STAT5 dependent chromatin remodeling in the T-cell activation response. Using publicly available data we found the chromatin response was far more dynamic at 24-h compared with 72-h post-activation. In total 546 associations were reproduced at both time-points with similar strength of evidence and directionality of effect. At the pathways level, the IL2-STAT5, KRAS signalling and UV response pathways were replicable at both time-points, although differentially modulated from 24 to 72 h post-activation.

Highlights

  • T-cell activation induces context-specific gene expression programs that promote energy generation and biosynthesis, progression through the cell cycle and cell differentiation

  • ATAC-seq integrated with transcription factors (TF) binding motifs has proven increasingly useful for uncovering the dynamic changes in enhancer landscapes and predicting key regulatory events that bring about chromatin remodeling

  • T-cell activation induces global remodeling of chromatin accessibility in an orderly and timely manner. These epigenetic changes are coincidental with specific gene regulatory networks that bring about changes in cellular metabolism, proliferative capacity and effector ­function[11]

Read more

Summary

Introduction

T-cell activation induces context-specific gene expression programs that promote energy generation and biosynthesis, progression through the cell cycle and cell differentiation. The aim of this study was to apply the omni ATAC-seq method to characterize the landscape of chromatin changes induced by T-cell activation in mature naïve CD4+ T-cells. T-cell receptor (TCR) signaling induces dynamic re-positioning of nucleosomes at promoters and enhancers to allow for transcriptional c­ hanges[5] These dynamic changes in the chromatin landscape enable interactions between sequence-specific transcription factors (TF) with regulatory DNA elements. In this study we isolated mature naïve T-cells from six healthy paediatric donors and studied chromatin dynamics in the canonical T-cell receptor signaling pathway using an identical protocol as published previously by ­us[19] This allowed us to analyze stimulation-dependent chromatin changes in the context of previously collected transcriptomic data. Our data are largely consistent with previous s­ tudies[20], demonstrating the utility of omni-ATAC for characterizing the enhancer landscape in paediatric bio-banked samples, as a prelude to future studies of disease mechanism

Objectives
Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call