Age-associated alterations in pro-inflammatory gene expression in humans

National Institute On Aging

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Abstract

The goal of the first phase of GESTALT was to obtain transcriptomic, proteomic and epigenomic data from 11 purified immune cell subsets obtained from peripheral blood. Sample collection for this phase was completed in February 2020. While the last sets of samples were being collected we began to analyze RNA, protein, DNA methylation and ATAC-Seq data from the first 54 samples. During FY23 we accomplished the following: We competed an analysis of DNA methylation changes that accrue with age in human immune cell subsets. Our observations point to a role for hypoxia in inducing differential age-associated patterns of methylation. This work has been accepted for publication. We completed an analysis of DNA methylation changes that take place during differentiation of naive B and T lymphocytes to the respective memory states. Previously we had found that a proportion of memory-specific DNA methylation changes in human CD4+ T cells resulted directly from cell proliferation. This was not the case for B ells. We hypothesized that CD4+ T cell memory may simply represent an expanded pool of antigen-specific cells, whereas B cell memory formation required additional steps of differentiation. Because B cells in germinal centers (GCs) are precursors to memory and effector (plasma) cells, we hypothesized that patterns of differential methylation during memory differentiation may be established on GC. We compared methylation states of memory cells to those of GC B cells and found that approximately 85% of the largest differences between naive and memory B cells were established in GCs. However, the remaining 15% that were specific to memory cells carried key hallmarks of B memory differentiation. These observations distinguish B cell-specific differential methylation from features shared with T cell memory. We continued studies of chromatin accessibility changes as a function of age in human immune cell subsets. Data analysis is complete for B cells and monocytes, and are being complied into manuscripts.