Environmental epigenomics and disease susceptibility

Key Points

  • Human epidemiological studies and animal investigations provide compelling evidence that prenatal and early postnatal environmental factors influence the adult risk of developing various chronic diseases, such as cancer, cardiovascular disease, diabetes, obesity and behavioural disorders such as schizophrenia.

  • The developmental origins of adult-onset disease hypothesis proposes that the evolution of developmental plasticity, which enables an organism to adapt to environmental signals during early life, can also increase the risk of developing chronic diseases when there is a mismatch between the perceived environment and that which is encountered in adulthood.

  • Epigenetics is the study of alterations in gene expression that occur not by changing the DNA sequence, but by modifying DNA methylation and remodelling chromatin structure.

  • Prenatal and postnatal environmental exposures could be linked to phenotypic changes later in life through the alteration of the epigenetic marks that regulate the functional output of the information that is stored in the genome.

  • In support of this postulate, maternal methyl-donor supplementation during pregnancy with folic acid, vitamin B12, choline and betaine was shown to effect the phenotype of the Avy (viable yellow agouti) offspring by directly altering the epigenome.

  • Studies with the fungicide vinclozolin demonstrate that heritable environmentally induced epigenetic modifications can also underlie transgenerational alterations in phenotype.

  • Novel genome-wide experimental and bioinformatic techniques are now being used to identify epigenetically labile genes in humans. Such approaches will hopefully allow for the development of unique epigenetic-based diagnostic, prevention and therapeutic strategies for human diseases.


Epidemiological evidence increasingly suggests that environmental exposures early in development have a role in susceptibility to disease in later life. In addition, some of these environmental effects seem to be passed on through subsequent generations. Epigenetic modifications provide a plausible link between the environment and alterations in gene expression that might lead to disease phenotypes. An increasing body of evidence from animal studies supports the role of environmental epigenetics in disease susceptibility. Furthermore, recent studies have demonstrated for the first time that heritable environmentally induced epigenetic modifications underlie reversible transgenerational alterations in phenotype. Methods are now becoming available to investigate the relevance of these phenomena to human disease.

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Figure 1: Epigenetic regulation of metastable epialleles.
Figure 2: Effect of maternal dietary supplementation on the phenotype and epigenotype of Avy/a offspring.
Figure 3: Epigenetic regulation of imprinted alleles.
Figure 4: Alterations in methylation status during development.
Figure 5: Germline transmission of epigenetically regulated transgenerational phenotypes.
Figure 6: A model for endocrine-disruptor-induced epigenetic transgenerational disease.


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The authors wish to thank D. Dolinoy for critically reading the manuscript and for her helpful suggestions. We thank J. Griffin for assistance in the preparation of this manuscript. This work was supported by grants from the US Department of Energy and the US National Institutes of Health.

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Refers to mitotically or meiotically heritable changes in gene expression that do not involve a change in DNA sequence.

DNA methylation

DNA methylation occurs predominantly in repetitive genomic regions that contain CpG residues. DNA methylation represses transcription directly by inhibiting the binding of specific transcription factors, and indirectly by recruiting methyl-CpG-binding proteins and their associated repressive chromatin-remodelling activities.

Histone modifications

Histones undergo post-translational modifications that alter their interaction with DNA and nuclear proteins. In particular, the tails of histones H3 and H4 can be covalently modified at several residues. Modifications of the tail include methylation, acetylation, phosphorylation and ubiquitination, and influence several biological processes, including gene expression, DNA repair and chromosome condensation.


Endogenous small RNAs of 22 nucleotides in length that act as a cellular rheostat for fine-tuning gene expression during development and differentiation. They target the 3′ UTRs of mRNAs with which they share partial sequence complementarity, leading to post-transcriptional gene silencing through translational repression. When a microRNA has complete sequence complementarity with a target mRNA, it instead directs cleavage of the transcript.

X-chromosome inactivation

The process that occurs in female mammals by which gene expression from one of the pair of X chromosomes is downregulated to match the levels of gene expression from the single X chromosome that is present in males. The inactivation process involves a range of epigenetic mechanisms on the inactivated chromosome, including changes in DNA methylation and histone modifications.

Genomic imprinting

The epigenetic marking of a locus on the basis of parental origin, which results in monoallelic gene expression.


The global epigenetic patterns that distinguish or are variable between cell types. These patterns include DNA methylation, histone modifications and chromatin-associated proteins.


A specialized cell type, lying at the boundary between the dermis and epidermis, in which the pigment melanin is synthesized.

Embryonic stem cell

A type of pluripotent stem cell that is derived from the inner cell mass of the early embryo. Pluripotent cells are capable of generating virtually all cell types of the organism.

Angelman syndrome

A defect that is caused by the loss of expression of a maternally expressed gene, UBE3A, which is imprinted only in the brain and encodes an E3 ubiquitin ligase. Angelman syndrome occurs in 1 in 15,000 births and its main characteristics include mental retardation, speech impairment and behavioural abnormalities.

Prader–Willi syndrome

The molecular defect that causes this syndrome is complex and involves defects that affect an 2 Mb imprinted domain that contains both paternally and maternally expressed genes. Prader–Willi syndrome occurs in 1 in 20,000 births and is characterized by a failure to thrive during infancy, hyperphagia and obesity during early childhood, mental retardation and behavioural problems.

Beckwith–Weidemann syndrome

A predominantly maternally transmitted disorder, involving fetal and postnatal overgrowth and a predisposition to embryonic tumours. The Beckwith–Weidemann syndrome locus includes several imprinted genes, including IGF2, H19 and KCNQ1, and loss of imprinting at IGF2 is seen in 20% of cases.

Bisulphite conversion

A technique that is used to identify methylcytosines. The approach depends on the relative resistance of the conversion of methylcytosine to uracil compared with cytosine. Conversion can be followed by PCR amplification and sequencing of the DNA. The persistence of a cytosine, instead of a thymine, being detected, reflects the methylation of the cytosine in the starting DNA sample.

Machine learning

The ability of a program to learn from experience — that is, to modify its execution on the basis of newly acquired information. In bioinformatics, neural networks and Monte Carlo Markov chains are well-known examples.

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Jirtle, R., Skinner, M. Environmental epigenomics and disease susceptibility. Nat Rev Genet 8, 253–262 (2007). https://doi.org/10.1038/nrg2045

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