Epigenetics lie behind the ability of human reproductive function to adapt to the environment

Addressing the mystery of how reproduction is shaped by childhood events and environment, Professor Philippa Melamed, together with Ph.D. student Ben Bar-Sadeh, Postdoctorate Dr. Sergei Rudnizky, and colleagues Dr. Lilach Pnueli and Professor Ariel Kaplan, all from the Technion Faculty of Biology, and collaborators from the UK, Professor Gillian R. Bentley from Durham University and Professor Reinhard Stöger from the University of Nottingham, have just published a paper in Nature Reviews Endocrinology on the role of epigenetics in human reproduction.

Epigenetics refers to the packaging of DNA, which can be altered in response to external signals (environment) through the addition of chemical “tags” to the DNA or the histone proteins that organize and compact the DNA inside the cell. This packaging affects the ability of a gene to be accessed and thus also its expression levels. So environmentally induced changes in this epigenetic packaging can lead to major variations in the phenotype (observable characteristics or traits) without changing the genetic code. This re-programming of gene expression patterns underlies some of our ability to adapt.

Reproductive characteristics are highly variable and responsive particularly to early life environment, during which they appear to be programmed to optimize an individual’s reproductive success in accordance with the surroundings. Although some of these adaptations can be beneficial, they also carry negative health consequences that may be far-reaching. These include the age of pubertal onset and duration of the reproductive lifespan for women, and also the levels of circulating reproductive hormones; not only is fertility affected, but also predisposition to hormone-dependent cancers and other age-related diseases.

While epigenetic modifications are believed to play a role in the plasticity of reproductive traits, the actual mechanisms are mostly still not clear. Moreover, reproductive hormones also modify the epigenome and epigenetic aging, which complicates distinguishing cause from effect, particularly when trying to understand human reproductive phenotypes in which the relevant tissues are inaccessible for analysis. Integrated studies are needed, including observations and whatever measurements are possible in human populations, incorporation of animal models, cell culture, and even single-molecule studies, in order to determine the mechanisms responsible for the human reproductive phenotype.

The review emphasizes that there is a clinical need to understand the characteristics of epigenetic regulation of reproductive function and the underlying mechanisms of adaptive responses for properly informed decisions on treating patients from diverse backgrounds. In addition, this knowledge should form the basis for formulating lifestyle recommendations and novel treatments that utilize the epigenetic pathway to alter a reproductive phenotype.

Prof. Melamed emphasizes that “a multifaceted cross-disciplinary approach is essential for elucidating the involvement of epigenetics in human reproductive function, spanning the grand scale of human cohort “big data” and anthropological studies in unique human populations, through animal models and cell culture experiments, to the exquisitely high resolution of single-molecule biophysical approaches. This will continue to require collaboration and co-operation.”

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