Chromatin accessibility differences of human monocyte identify age associated inflammatory heterogeneity.

Abstract

Abstract Human aging is associated with low grade chronic inflammation termed, inflammaging, which is a significant risk factor for morbidity and mortality in elderly. The innate immune system is master regulator of this process via regulating expression of cytokines and other key mediators. We assayed chromatin landscape of the human monocytes during healthy aging with an aim to predict the inflammation associated contemporary and imminent states of monocytes. Our deep sequencing ATAC-seq data from healthy donors of the GESTALT cohort identified, chromatin landscape signatures defining heterogeneity of monocytes. Differentially open chromatin (DOC) clustered old individual monocytes in two distinct groups, while young donors demonstrated ethnicity-based differences. DOC’s heterogeneity of old donors was characterized by presence of intergenic enhancer-like elements dominated by the DNA binding motif of the transcription factor NF-κB. We identified the relationships of age-associated DOC with DNA methylation, gene expression and proteome of monocytes and serum. Finally, the intracellular cytokine staining analysis using multi-parameter flow cytometry demonstrated the DOC’s influence on the monocyte’s response to LPS stimulation. Our data revels the age associated heterogenous functional states of monocytes which can help us understanding decision making mechanisms during an immune response.