The epigenome is not as sensitive to the environment as previously thought

Early-life exposure of an individual to the environmental factors (e.g., maternal high fat diet, toxicant exposure, folic acid deficiency) is thought to influence the epigenome or chemical marks on their DNA (e.g. methylation) that control how genes are expressed. If environmentally-induced changes in DNA methylation occur in key regions of the epigenome, genes might be misexpressed leading to an increased risk of disease. The extent to which environment factors affect the epigenome is unclear.

Retrotransposons are genetic features that have the ability to copy and paste themselves into different locations of the genome and are sometimes incorporated into regulatory regions that control gene expression. For this reason, retrotransposons show high levels of DNA methylation and are thought to remain this way throughout an individual’s lifetime. This is because dysregulation of retrotransposons increase the risk for mutation and disease. However, there is a group of retrotransposons called variably methylated intracisternal A-particle (VM-IAP) that naturally show differences in DNA methylation levels between individuals and might be the key to understanding traits and disease risk varies amongst a group of people. One VM-IAP called the Agouti Viable Yellow (A^vy) allele was classically shown to demonstrate sensitivity to environmental factors, and many of our conclusions about VM-IAPs come from this one example.

A collaborative study recently published in Nature Genetics between the Ferguson-Smith lab (Department of Genetics), Watson lab (Department of Physiology, Development, and Neuroscience), and Ozanne lab (Metabolic Research Laboratories) at the University of Cambridge and labs at the University of Philadelphia, USA, shows that when a broad group of VM-IAPs are assessed in mice, that they are not as sensitive to environmental factors as previously thought. Although DNA methylation at VM-IAPs is different between individuals (as expected), it remained at the same level across an individual’s lifespan indicating that VM-IAP methylation was resistant to aging. Furthermore, fetuses exposed to a high fat diet or the toxicant bisphenol A in utero showed no significant changes in DNA methylation within VM-IAPs. Similarly feeding pregnant females a methionine-rich diet, which provides excess methyl groups required for methylation, did not influence VM-IAP methylation. This result challenges the dogma and suggests that VM-IAPs, when considered outside of the classic example of the A^vy allele, are not sensitive to environmental changes over the course of an individual’s lifetime and that VM-IAPs are not biosensors of the environment.

The researchers also assessed VM-IAP methylation in a mouse model (the Mtrr^gt mouse line) whereby folate (also known as folic acid) metabolism is genetically disrupted to cause similar effects as folate deficiency. They found that patterns of VM-IAP methylation were substantially altered compared to the control group. While this result is in part due to the fact that folate metabolism is for all methylation reactions in the cell including DNA methylation, they also showed that the underlying genomic sequence likely plays a part in altering VM-IAP methylation. This is based upon the evidence of how this mouse line was generated and the genetic sequence around the mutation site that includes a family of regulatory proteins (KRAB-ZFP transcription factors) that are known to be involved in the regulation of VM-IAPs. Since this mouse line is used to study the multigenerational effects of folate on development, the results indicate that a complex interaction between the epigenome and the genome that will need to be teased apart to better understand multigenerational effects.

Reference: Bertozzi TM, Becker JL, Blake GET, Bansal A, Nguyen DK, Fernandez-Twinn DS, Ozanne SE, Bartolomei MS, Simmons RA, Watson ED, and Ferguson-Smith AC. Variably methylated retrotransposons are refractory to a range of environmental perturbations. Nature Genetics doi: 10.1038/s41588-021-00898-9