Genetic determinants of co-accessible chromatin regions in activated T cells across humans

Abstract

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4 T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, consistent with the three-dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression.

Predicting cell-type-specific non-coding RNA transcription from genome sequence

“…Although enhancer RNA QTL might be partly discovered from ChIP-seq for histone 5 marks (e.g., H3K4me1 and H3K27ac), DNase-seq or ATAC-seq, these studies have also been conducted for LCL, blood cells, and other limited types of cells using only hundreds of European or Yoruba individuals (Alasoo et al, 2018;Banovich et al, 2018;Bryois et al, 2018;Degner et al, 2012;Delaneau et al, 2019;Gate et al, 2018;Kumasaka et al, 2019;Pelikan et al, 2018). An alternative approach is the 10 experimental identification of transcribed enhancers (van Arensbergen et al, 2019), but it would still be challenging to conduct such experiments in many types of cells.…”

Development of circulating CD4+ T‐cell memory

“…Given that the degree to which chromatin is open for transcription factor binding plays an important role in whether any given gene can be expressed in T cells, quantitative assessment of chromatin accessibility is likely to be extremely useful for the study of T‐cell memory. The advent of Assay for Transposase Accessible Chromatin using sequencing has already provided initial insights into human peripheral blood CD4 + T cells . We anticipate that Assay for Transposase Accessible Chromatin using sequencing profiling at bulk and single‐cell levels will provide many new insights into memory CD4 + T cells in humans and experimental animal models.…”

“…The advent of Assay for Transposase Accessible Chromatin using sequencing 41 has already provided initial insights into human peripheral blood CD4 + T cells. 42,43 We anticipate that Assay for Transposase Accessible Chromatin using sequencing profiling at bulk and single-cell levels will provide many new insights into memory CD4 + T cells in humans and experimental animal models.…”

Mapping gene regulatory networks of primary CD4+T cells using single-cell genomics and genome engineering

“…1A; Methods). Activated cells were transfected with 280 sgRNAs targeting 140 regulators that were either highly expressed (top quartile from bulk RNA-seq) or have binding sites that were differentially accessible (from bulk ATAC-seq) in activated CD4 + T cells (18) (Fig. 1B; Table 1; Methods).…”

“…While the functionalization of CD4 + T cells is predominantly determined by the polarization of naive T cells (T naive ), recent results have suggested a high degree of variation within and plasticity between canonical subtypes (17). Indeed, we (18,19) and others (20)(21)(22) have shown that human circulating CD4 + T cells are composed of a mixture of canonical and non-canonical populations with significant interindividual variability in both the proportion and gene expression of each population (18).…”