"The proper study of mankind is man."

Alexander Pope

Large-scale epigenomics in human cohorts

To paraphrase Pope's statement, a complete understanding of diseases afflicting the humankind requires the study of living humans. However, humans are exposed to countless and often uncontrollable environmental stimuli, including day-to-day stressors, that can affect the epigenome in subtle and complex ways. To disentangle such complexity with the highest precision possible, we conduct large-scale epigenomic analyses through established collaborations with human cohorts that have well-documented stress exposure and disease outcomes. Participating cohorts include several studies affiliated with the Trans-Omics for Precision Medicine (TOPMed) program, the longitudinal AURORA (Advancing Understanding of RecOvery afteR traumA) study, cohorts of the Psychiatric Genomics Consortium, and populations undergoing chronic caregiving stress (total >30,000 participants with available epigenetic and phenotypic data to date). Key epigenetic signatures identified by these large-scale analyses are mechanistically dissected in relevant experimental systems.

Representative examples from our cohort studies examining epigenetic regulation at stress-responsive and inflammation-related genes along the human lifespan (adapted from: Palma-Gudiel et al., Brain, Behavior, and Immunity, 2021; Zannas et al., PNAS, 2019).

Mechanistic investigations in cell models

While studies in human cohorts can identify the epigenetic signatures associated with stress, well controlled experiments are necessary to uncover the fundamental mechanisms underlying these associations. Such fundamental studies call for cell models carefully designed to address disease-relevant questions. Our lab employs innovative approaches to model certain aspects of stress exposure and aging-related disease in cell culture. Examples include the stimulation of immune cells and the prolonged exposure of fibroblasts to stress hormones at levels known to be reached in human tissues during stress exposure. To dissect epigenetic mechanisms, stress hormone exposures are combined with high-throughput quantification of cell phenotypes and targeted DNA methylation editing of key stress-regulated genes. Despite the limitations inherent in using cells as reductionist models of disease, such mechanistic investigations in combination with convergent analyses in living humans can vertically advance the way we conceptualize stress-related conditions.

Examples from our experiments dissecting how chronic exposure to physiological stress hormone levels shapes key cell phenotypes and cumulative epigenetic patterns (adapted from: Leung et al., iScience, 2022; Zannas, IJMS, 2021).

Cross-species translation of stress epigenetics

We further aim to extend and translate the insights gained from our human and cell studies with the convergent use of model organisms that undergo experimental stress exposure and other manipulations. This aim is accomplished through established collaborations of our laboratory with other UNC principal investigators and labs participating in the Carolina Stress Initiative, a translational initiative of the UNC Department of Psychiatry that aims to unravel the mechanistic underpinnings of stress-related conditions.

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