Social regulation of gene expression in human leukocytes

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-kappaB/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.

Figure 1

Differential gene expression in high- versus low-lonely individuals. Genome-wide transcriptional profiles were assessed in peripheral blood leukocyte RNA samples collected from individuals in the top and bottom 15% of the distribution of subjective social isolation. Analysis by Affymetrix U133A high-density oligonucleotide arrays identified 209 transcripts showing >30% difference in mean expression levels across groups (green = over-expression in high-lonely, red = under-expression). High subjective social isolation is associated with a statistically significant net reduction in the number of expressed genes (131 down-regulated versus 78 up-regulated, p value by exact binomial test).

Figure 2

Transcriptional activity of GR and NF-κB signaling pathways. TELiS bioinformatics analysis assessed trans-activational activity based on the relative prevalence of GR and NF-κB response elements in the promoters of all 209 transcripts over-expressed in high- versus low-lonely individuals (data represent mean ± standard error prevalence of response elements within promoters from each group). Contributions of in-trans regulatory influences to the observed inverse skew of NF-κB and GR response elements within differentially expressing promoters was tested by comparison to a null distribution of genome-wide DNA cis-structural associations generated by 10,000 random samples of 209 transcripts assayed by Affymetrix U133A arrays.

Figure 3

Transcription control pathways differentially active in high- versus low-lonely individuals. Data represent the mean (± standard error) prevalence of transcription factor-binding motifs in primary TELiS bioinformatics analysis of genes over-expressed in leukocytes from high- versus low-lonely individuals.