Multi-level remodelling of chromatin underlying activation of human T cells

Naiara G Bediaga,Hannah D Coughlan,Gordon K Smyth,Timothy M Johanson,Liam G Fearnley,Jan Schröder,Esther Bandala-Sanchez,Leonard C Harrison,Gaetano Naselli,Alexandra L Garnham,Rhys S Allan

doi:10.1038/s41598-020-80165-9

Abstract

Remodelling of chromatin architecture is known to regulate gene expression and has been well characterized in cell lineage development but less so in response to cell perturbation. Activation of T cells, which triggers extensive changes in transcriptional programs, serves as an instructive model to elucidate how changes in chromatin architecture orchestrate gene expression in response to cell perturbation. To characterize coordinate changes at different levels of chromatin architecture, we analyzed chromatin accessibility, chromosome conformation and gene expression in activated human T cells. T cell activation was characterized by widespread changes in chromatin accessibility and interactions that were shared between activated CD4+ and CD8+ T cells, and with the formation of active regulatory regions associated with transcription factors relevant to T cell biology. Chromatin interactions that increased and decreased were coupled, respectively, with up- and down-regulation of corresponding target genes. Furthermore, activation was associated with disruption of long-range chromatin interactions and with partitioning of topologically associating domains (TADs) and remodelling of their TAD boundaries. Newly formed/strengthened TAD boundaries were associated with higher nucleosome occupancy and lower accessibility, linking changes in lower and higher order chromatin architecture. T cell activation exemplifies coordinate multi-level remodelling of chromatin underlying gene transcription.

Highlights

Remodelling of chromatin architecture is known to regulate gene expression and has been well characterized in cell lineage development but less so in response to cell perturbation
Activation-induced changes were explored by comparing activated to resting T cells and the statistical significance of the changes was determined with the e dgeR16 and limma[17] software packages, controlling the false discovery rate relative to biological variability between the individual donors
Activation of T cells was associated with multi-level remodelling of chromatin that was comparable between CD4+ and CD8+ T cells, indicating that their activation is regulated by similar genome control mechanisms

Summary

Introduction

Remodelling of chromatin architecture is known to regulate gene expression and has been well characterized in cell lineage development but less so in response to cell perturbation. To characterize coordinate changes at different levels of chromatin architecture, we analyzed chromatin accessibility, chromosome conformation and gene expression in activated human T cells. Chromosomes are organized into a gene-rich, transcriptionally active compartment (A) with open chromatin and active histone marks and a gene-poor, transcriptionally inactive compartment (B) with condensed chromatin and gene silencing histone marks Within this overall organization, the interplay between chromatin s tructure[8] and gene expression[9,10,11] is cell-specific and mediated by transcription factors (TFs) and other DNA binding proteins the functions of which depend on chromatin accessibility. We analyse genome-wide chromosome conformation in conjunction with chromatin accessibility and whole transcriptome expression to further understand how coordinated changes across different levels of chromatin structure are linked to gene expression in response to T cell activation

Methods

Results

Conclusion