November 16, 2015

Affecting health across generations

Antoine Peters and his group at the Friedrich Miescher Institute for Biomedical Research (FMI), in collaboration with scientists from Canada, have shed new light on paternal epigenetic inheritance. Experiments in a mouse model show that the development of offspring can be severely impaired by alterations in chromatin and gene expression in developing male germ cells. These findings, just published in Science, have the potential to change our understanding of the mechanisms whereby traits are inherited.

Women considering pregnancy are usually well informed about recommended health measures – stopping smoking, eating a balanced diet and taking regular exercise. Prospective fathers have been less aware of how they contribute to future children’s health. An increasing number of studies suggest that men’s influence may go beyond their genetic contribution. In recent years, it has been shown that a father’s experiences in relation to food, drugs and stress —even before a child is conceived — can affect the development and health of his children, and sometimes even grandchildren. But, despite a decade of research in this area, the mechanisms underlying the transmission of “environmental memories” across several generations remain largely unclear.

Researchers in the field of epigenetics are currently focusing on a small number of possible molecular mechanisms for so-called transgenerational inheritance – chemical modifications of DNA and of histones (protein spools around which DNA is wound) and various kinds of RNA.

To investigate mechanisms of paternal inheritance, Sarah Kimmins and colleagues at McGill University (Montreal), together with Antoine Peters and his group at the FMI, focused on the role of histones – proteins that allow DNA to be compacted and organized into tightly coiled structures known as chromatin. Histones are subject to various chemical modifications that regulate the extent to which DNA is compacted. One such modification is methylation, which affects different histone residues and has been implicated in the control of gene expression. It has also been proposed that methylation marks contribute to the inheritance of active and repressed transcriptional states across generations of cells and organisms.

The packaging of DNA is particularly remarkable in sperm, where the whole genome is fitted into a tiny head, ready for fertilization. While the majority of the DNA in sperm is bound to protamines – which permit much tighter packaging – human and mouse sperm respectively contain about 15% and 1% of the histones normally present in somatic cells. Previous studies by Antoine Peters’ team and others have shown that histones in human and mouse sperm are not randomly distributed over the genome but are enriched at sequences that control gene expression, suggesting that paternal transmission of epigenetic information could possibly be controlled by modifications of these proteins.

To study the role of histone methylation in inheritance, the scientists generated transgenic mice in which the enzyme lysine demethylase 1A (KDM1A) is overexpressed during spermatogenesis. KDM1A is well known for its ability to remove two methyl groups from lysine 4 of histone 3 (H3K4me2), a modification associated with gene expression. Commenting on the effects observed, co-lead author Peters says: “The offspring showed profound consequences in terms of their development — they were prone to birth defects including abnormal skeletal formation — and survival. But what surprised us most was the fact that we observed similar defects in grandchildren, even when the KDM1A enzyme had only been expressed in developing germ cells of the grandfather, but not of the father.”

Overexpression of KDM1A during spermatogenesis was found to be associated with reduced H3K4 dimethylation in more than 2300 genes, including many regulatory genes playing an important role in development. These changes were observed in transgenic males where KDM1A was overexpressed in developing sperm, but not in non transgenic brothers that had not inherited the KDM1A gene from their father. This observation is surprising since the health of the offspring of the non-transgenic brothers was also impaired. This suggests that changes in H3K4me2, as observed in mature sperm of transgenic fathers, were not directly driving the aberrant phenotypes in offspring.

However, as Peters points out: “We observed altered RNA profiles in sperm of transgenic and non-transgenic siblings and their embryonic offspring. In contrast, methylation of DNA at a particular class of regulatory sites in the genome – so-called CpG islands, commonly implicated in epigenetic inheritance – was not altered in sperm of transgenic and non-transgenic siblings. Our work thus shows that epigenetic inheritance of aberrant development can be initiated by histone demethylase activity in developing germ cells, resulting in changes in RNA content in sperm but leaving DNA methylation at CpG-rich regions unaltered.”

With the new model, the role of histone methylation in developing germ cells and early embryos can be further dissected. “Given the complex nature of the regulation of inheritance,” says Peters, “we will look in much greater mechanistic detail to elucidate causal relationships.”

And what does this mean for prospective fathers? Peters explains: “Our study was designed to investigate how the development of offspring is affected by altered histone modification states and gene regulation in developing male germ cells. Since certain histone modifications are susceptible to environmental exposures, our work opens up new avenues for investigation. Pre-conception health may become increasingly relevant for males too.”

Original publications
Siklenka K, Erkek S, Godmann M, Lambrot R, McGraw S, Lafleur C, Cohen T, Xia J, Suderman M, Hallett M, Trasler J, Peters AHFM, Kimmins S. (2015) Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science DOI: 10.1126/science.aab2006

About Antoine Peters
Antoine Peters is a Senior group leader at the FMI and Adjunct Professor of Epigenetics at the University of Basel. He aims to elucidate the epigenetic mechanisms regulating cell fate choices during mammalian germ cell and early embryonic development. In particular, he is interested in the processes that control the formation of the totipotent embryo after the fusion of an oocyte and a spermatozoon, two differentiated and transcriptionally silent germ cells.
More on Antoine Peters

About this site2018 © FMI Basel Switzerland