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Cell Types in Environmental Epigenetic Studies: Biological and Epidemiological Frameworks

  • Early Life Environmental Health (H Volk and J Buckley, Section Editors)
  • Published:
Current Environmental Health Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This article introduces the roles of perinatal DNA methylation in human health and disease, highlights the challenges of tissue and cellular heterogeneity to studying DNA methylation, summarizes approaches to overcome these challenges, and offers recommendations in conducting research in environmental epigenetics.

Recent Findings

Epigenetic modifications are essential for human development and are labile to environmental influences, especially during gestation. Epigenetic dysregulation is also a hallmark of multiple diseases. Environmental epigenetic studies routinely measure DNA methylation in readily available tissues. However, tissues and cell types exhibit specific epigenetic patterning and heterogeneity between samples complicates epigenetic studies. Failure to account for cell-type heterogeneity limits identification of biological mechanisms and biases study results.

Summary

Tissue-level epigenetic measures represent a convolution of epigenetic signals from individual cell types. Tissue-specific epigenetics is an evolving field and the use of disease-affected target, surrogate, or multiple tissues has inherent trade-offs and affects inference. Likewise, experimental and bioinformatic approaches to accommodate cell-type heterogeneity have varying assumptions and inherent trade-offs that affect inference. The relationships between exposure, disease, tissue-level DNA methylation, cell type–specific DNA methylation, and cell-type heterogeneity must be carefully considered in study design and analysis. Causal diagrams can inform study design and analytic strategies. Properly addressing cell-type heterogeneity limits sources of potential bias, avoids misinterpretation of study results, and allows investigators to distinguish shifts in cell-type proportions from direct changes to cellular epigenetic programming, both of which provide insights into environmental disease etiology and aid development of novel methods for prevention and treatment.

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Funding

K. A. C. was supported by the National Institutes of Health (T32 HG00040) and Michigan State University’s Environmental Influences on Child Health Outcomes program (UG3 OD023285, UH3 OD023285). J. A. C. was supported by the Ravitz Family Foundation, the Forbes Institute for Cancer Discovery at the University of Michigan Rogel Cancer Center, and the National Institutes of Health (grant numbers R01 ES028802, U01 ES026697, P30 ES017885, and P30 CA046592). S. K. P. declares no funding sources. K. M. B. was supported by research grants from the National Institute of Environmental Health Sciences (R01 ES025531; R01 ES025574), National Institute of Aging (R01 AG055406), National Institute on Minority Health and Health Disparities (R01 MD013299), and ALS Association (20-IIA-532).

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  1. Department of Epidemiology, University of Michigan School of Public Health, University of Michigan, Ann Arbor, MI, USA

    Kyle A. Campbell, Sung Kyun Park & Kelly M. Bakulski

  2. Department of Environmental Health Sciences, University of Michigan School of Public Health, University of Michigan, Ann Arbor, MI, USA

    Justin A. Colacino & Sung Kyun Park

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  1. Kyle A. Campbell
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Correspondence to Kyle A. Campbell.

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Campbell, K.A., Colacino, J.A., Park, S.K. et al. Cell Types in Environmental Epigenetic Studies: Biological and Epidemiological Frameworks. Curr Envir Health Rpt 7, 185–197 (2020). https://doi.org/10.1007/s40572-020-00287-0

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