Social regulation of human gene expression: mechanisms and implications for public health

Abstract

Recent analyses have discovered broad alterations in the expression of human genes across different social environments. The emerging field of social genomics has begun to identify the types of genes sensitive to social regulation, the biological signaling pathways mediating these effects, and the genetic polymorphisms that modify their individual impact. The human genome appears to have evolved specific "social programs" to adapt molecular physiology to the changing patterns of threat and opportunity ancestrally associated with changing social conditions. In the context of the immune system, this programming now fosters many of the diseases that dominate public health. The embedding of individual genomes within a broader metagenomic network provides a framework for integrating molecular, physiologic, and social perspectives on human health.

FIGURE 1—

Social signal transduction. Note. Socioenvironmental conditions regulate human gene expression by activating central nervous system processes that subsequently influence hormone and neurotransmitter activity in the periphery of the body. Peripheral signaling molecules interact with cellular receptors to activate transcription factors, which bind to characteristic DNA motifs in gene promoters to initiate (or repress) gene expression. Only genes that are transcribed into RNA actually have an impact on health and behavioral phenotypes. Individual differences in promoter DNA sequences (e.g., the [G/C] polymorphism shown here) can affect the binding of transcription factors and thereby influence genomic sensitivity to socioenvironmental conditions.

FIGURE 2—

Social regulation of gene expression in human immune cells. Note. Red = high expression; black = intermediate expression; green = low expression. Expression of 22 283 human gene transcripts was assayed in approximately 10 million blood leukocytes sampled from each of 14 older adults who showed consistent differences over 4 years in their level of subjective social isolation. Two hundred nine gene transcripts showed differences of 30% or more in average expression level in leukocytes from 6 people experiencing chronic social isolation versus 8 people experiencing consistent social integration. In this heat plot, each row represents data from 1 of the 14 study participants, each column contains expression values for 1 of the 209 differentially active genes, and the coloring of each cell represents the relative level of that gene’s expression in a given participant’s leukocyte sample. Source. Adapted from Cole et al.

FIGURE 3—

RNA as a molecular medium of recursive development. Note. Social conditions at one point in time (Environment₁) are transduced into changes in behavior (Behavior₁) and gene expression (RNA₁) via central nervous system perceptual processes that trigger systemic neural and endocrine responses (mediated by Body₁). Those RNA transcriptional dynamics may alter molecular characteristics of cells involved in environmental perception or response, resulting in a functionally altered Body₂. Body₂ may respond differently to a given environmental challenge than would the previous Body₁, resulting in different behavioral (Behavior₂) and RNA transcriptional responses (RNA₂). The persisting effect of RNA transcriptional dynamics on cellular protein and functional characteristics provides a molecular framework for understanding how socioenvironmental conditions in the past may continue to affect current behavior and health and how those historical conditions interact with current environments to shape one’s future trajectories (e.g., Body₃, Behavior₃, RNA₃). Because gene transcription serves as both a cause of social behavior (by shaping Body) and a consequence of social behavior (a product of environment × body), RNA constitutes the physical medium for a recursive developmental trajectory that integrates genetic characteristics and historical–environmental regulators to understand individual biological and behavioral responses to current environmental conditions.