Mother's epigenetic memory essential for embryo development and survival

Friday, 14 July, 2017


It has long been debated if epigenetic modifications accumulated throughout the entire life can cross the border of generations and be inherited by children or even grandchildren.

Now, researchers from Australia and Germany have found robust evidence that not only inherited DNA itself but also inherited epigenetic instructions contribute to regulating gene expression in offspring. Moreover, the new insights describe for the first time biological consequences of this inherited information.

The new study, published in Science, prove that mother’s epigenetic memory is essential for the development and survival of the new generation. It was led by Dr Nicola Iovino at the Max Planck Institute of Immunobiology and Epigenetics and co-authored by Dr Ozren Bogdanovic from Sydney’s Garvan Institute of Medical Research.

The researchers used the fruit fly Drosophila to investigate how instructions other than DNA are passed from parent fruit flies to their offspring. They found that additional instructions are contained in the proteins that package DNA and that not only are these instructions carried to the next generation, but their inheritance is essential for the completion of embryo development and survival.

The team focused on a particular modification called H3K27me3, which can also be found in humans. It alters the so-called chromatin, the packaging of the DNA in the cell nucleus, and is mainly associated with repressing gene expression.

The scientists used an advanced genome-wide method called ChIP-seq, which sequences a cell’s DNA and precisely maps the location of bound proteins.

They found that H3K27me3 modifications labelling chromatin DNA in the mother’s egg cells were still present in the embryo after fertilisation, even though other epigenetic marks are erased. “This indicates that the mother passes on her epigenetic marks to her offspring. But we were also interested if those marks are doing something important in the embryo,” explained Fides Zenk, first author on the study.

The researchers were then able to delete the histone marks from embryos by blocking the cellular enzyme that deposits the marks, and were very surprised by their findings.

“Embryo development simply couldn’t progress without these epigenetic marks, meaning H3K27me3 is not only inherited, it is an essential regulator of development and vital for embryo survival,” said Dr Bogdanovic.

“In reproduction, when an egg is fertilised by a sperm cell, it undergoes extensive epigenetic reprogramming, and for a long time it was assumed that any epigenetic traces from the parents were wiped away, leaving a clean DNA slate. This study definitively shows that this is not the case — we need some parental epigenetic traces to be left behind.

“Without this extra level of information, cells can’t interpret the DNA blueprint and an organism cannot form.”

This is one of only a very few conclusive reports to demonstrate epigenetic mechanisms of transgenerational inheritance in animals, and the first one to comprehensively reveal the biological consequences of the loss of such a mechanism.

As noted by Dr Bogdanovic, fruit flies have many biological mechanisms that are very similar to those in humans. He said, “Thousands of fruit fly genes have human equivalents, so it is likely that what we observe in fruit flies is also happening in some way in people.”

Human DNA contains approximately 20,000 genes, which are programmed to produce an estimated two million types of proteins. Deciphering how the epigenetic mechanisms of controlling these genes are inherited down through generations is a growing area of research.

“We are just beginning to understand these mechanisms; until now, the role of histone modifications has been largely overlooked. While H3K27me3 plays a role in early embryo development, it is likely just one of many histone marks that can be transmitted down through generations, and others are likely to affect different stages of development, different organs or different biological processes,” said Dr Bogdanovic.

Professor Susan Clark, head of Garvan’s Genomics and Epigenetics Division and president of the Australian Epigenetics Alliance, said the findings have far-reaching implications.

“This works signifies a huge step forward in our understanding of transgenerational epigenetic inheritance and may in part explain how the food we eat, the stresses we endure and our overall lifestyle could impact on the health of future generations,” Professor Clark said.

“We are delighted that Dr Bogdanovic has recently moved to Garvan to establish his own laboratory, where he and his team will continue to investigate the role of epigenetics in human health.”

Image caption: Egg cell of a female fruit fly with the egg cell in which H3K27me3 was made visible through green staining. This cell, together with the sperm, will contribute to the formation of the next generation of flies. In the upper-right corner, a maternal and paternal pre-nucleus are depicted before their fusion during fertilisation. The green colouration of H3K27me3 appears exclusively in the maternal pre-nucleus, indicating that their epigenetic instructions are inherited by the next generation. ©MPI of Immunobiology and Epigenetics/F Zenk

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