Social regulation of gene expression in human leukocytes

TLDR

Social environmental influences on human health are well established in epidemiology, yet the functional genomic mechanisms remain unclear. The study aimed to determine whether chronic loneliness alters transcription control pathways that could elevate adverse health outcomes. Genome‑wide transcriptional activity was examined in leukocytes from individuals reporting high versus low subjective social isolation using microarray profiling. Microarray analysis of 14 high‑lonely versus 14 low‑lonely participants identified 209 differentially expressed genes, with up‑regulation of immune activation, transcription control, and cell‑proliferation genes and down‑regulation of mature B‑cell and type‑I interferon genes, and promoter analysis revealed reduced glucocorticoid‑responsive genes and increased NF‑κB/Rel‑responsive genes—a pro‑inflammatory shift not attributable to cortisol or other covariates, suggesting altered transcriptional control underlies the heightened inflammatory disease risk in chronically lonely individuals.

Abstract

Abstract Background Social environmental influences on human health are well established in the epidemiology literature, but their functional genomic mechanisms are unclear. The present study analyzed genome-wide transcriptional activity in people who chronically experienced high versus low levels of subjective social isolation (loneliness) to assess alterations in the activity of transcription control pathways that might contribute to increased adverse health outcomes in social isolates. Results DNA microarray analysis identified 209 genes that were differentially expressed in circulating leukocytes from 14 high- versus low-lonely individuals, including up-regulation of genes involved in immune activation, transcription control, and cell proliferation, and down-regulation of genes supporting mature B lymphocyte function and type I interferon response. Promoter-based bioinformatic analyses showed under-expression of genes bearing anti-inflammatory glucocorticoid response elements (GREs; p = 0.032) and over-expression of genes bearing response elements for pro-inflammatory NF-κB/Rel transcription factors ( p = 0.011). This reciprocal shift in pro- and anti-inflammatory signaling was not attributable to differences in circulating cortisol levels, or to other demographic, psychological, or medical characteristics. Additional transcription control pathways showing differential activity in bioinformatic analyses included the CREB/ATF, JAK/STAT, IRF1, C/EBP, Oct, and GATA pathways. Conclusion These data provide the first indication that human genome-wide transcriptional activity is altered in association with a social epidemiological risk factor. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of subjective social isolation.