Journal of Molecular Endocrinology (2011) 46, R11-R32
0952-5041/11/046-R11 © 2011 Society for Endocrinology Printed in Great Britain
Xiang Zhang and Shuk-Mei Ho shuk-mei.ho at uc.edu
Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Kettering Complex
Although genetics determines endocrine phenotypes, it cannot fully explain the great variability and reversibility of the system in response to environmental changes.
Evidence now suggests that epigenetics, i.e. heritable but reversible changes in gene function without changes in nucleotide sequence, links genetics and environment in shaping endocrine function.
Epigenetic mechanisms, including DNA methylation, histone modification, and microRNA, partition the genome into active and inactive domains based on endogenous and exogenous environmental changes and developmental stages, creating phenotype plasticity that can explain interindividual and population endocrine variability.
We will review the current understanding of epigenetics in endocrinology, specifically, the regulation by epigenetics of the three levels of hormone action (synthesis and release, circulating and target tissue levels, and target-organ responsiveness) and the epigenetic action of endocrine disruptors.
We will also discuss the impacts of hormones on epigenetics. We propose a three-dimensional model (genetics, environment, and developmental stage) to explain the phenomena related to progressive changes in endocrine functions with age, the early origin of endocrine disorders, phenotype discordance between monozygotic twins, rapid shifts in disease patterns among populations experiencing major lifestyle changes such as immigration, and the many endocrine disruptions in contemporary life.
We emphasize that the key for understanding epigenetics in endocrinology is the identification, through advanced high-throughput screening technologies, of plasticity genes or loci that respond directly to a specific environmental stimulus. Investigations to determine whether epigenetic changes induced by today’s lifestyles or environmental ‘exposures’ can be inherited and are reversible should open doors for applying epigenetics to the prevention and treatment of endocrine disorders.
Figure 3 Genetics, environment, and stages of lifespan development interact in a three-dimensional space to create discordant endocrine phenotypes (epigenomes) from an identical genetic background (a single genome).
Here, we use five pairs of monozygotic twins, in a schematic representation, to illustrate our understanding of this model.
We applied the concept of principal component analysis to generate this diagram.
The traditional view that an individual’s phenotype is controlled solely by genetics (x-axis) is represented by two twin pairs A and B.
According to this gene-centric view, the two twin pairs will have identical phenotypes despite continuous changes in their environment (z-axis) and over developmental time (y-axis). The more contemporary view argues that the interactions among genetics, the environment, and the developmental stages during the lifespan produce two different epigenomes, hence phenotypes, over developmental time in the twin pairs, albeit their identical genome at conception. The divergence of the phenotypes (epigenomes) of the twin pairs varies depending on the degree of environmental variations. Phenotype discordance is greatest in the E twin pair as compared with the C and D twin pairs (smallest variation), in agreement with their environmental variation. With advance in age (developmental time), their divergence in phenotype also expands. This model gives the various stages of lifespan development different weights to reflect their susceptibility to epigenetic modifications.