The chromatin accessibility signature of aging in human blood leukocytes stem from CD8+ T cells.

Abstract

Human aging is linked to changes in immune function that contribute to decreased responses to pathogens and increased systemic inflammation. Human aging is also associated with profound epigenetic changes across cell types and tissues. How these changes affect the aging –associated decline of the immune system is unknown. The Assay for Transposase Accessible Chromatin with sequencing technology (ATAC-seq) allowed us to study, at a system biology level, the open chromatin landscapes of human peripheral blood mononuclear cells (PBMCs), monocytes, purified B and T cell subsets from healthy young and healthy elderly individuals. We captured aging-associated epigenomic remodeling in PBMCs consisting of (1) systematic chromatin closing at promoters and enhancers targeting the T cell signaling and development and (2) chromatin opening, mostly at quiescent and repressed sites associated with cytotoxicity. Transcriptome profiling of the same individuals revealed gene expression changes concordant with epigenomic changes. Analysis of naïve and memory CD4+ and CD8+ T cell subsets demonstrated that the epigenomic signature of aging in PBMCs arises mostly from memory CD8+ T cells, indicating that aging differentially affects T cell epigenomes in a subset-specific manner. This study provides the first systems-level description of chromatin accessibility changes associated with immune aging in human PBMCs and T cell subsets. It revealed in PBMCs significant chromatin closing at promoters and enhancers, including at the IL7R locus and the IL-7 signaling pathway. Our study revealed individual-level variability in aging-associated chromatin remodeling and provided a systematic and modular tool for assessing deviations from chronological age. The open chromatin profiling of sorted T cell subsets, concluded that the chromatin “aging signature” captured in PBMCs, mostly stems from memory CD8+ T cells. The combined ATAC-seq/RNA-seq analyses uncovered epigenetic changes poised for expression changes and active noncoding elements (e.g., enhancers), both of which will be essential for understanding the regulatory mechanisms underlying immunosenescence. Nevertheless, ATAC-seq based open chromatin profiling is a straightforward approach to identify functional genomic regulatory regions, master regulators, and gene regulatory networks controlling complex in vivo processes. In our lab, ATAC-seq is utilized to understand the epigenetics differences in different immune cells and diseases.