How does DNA affect heredity

Inheritance Beyond DNA: Epigenetic Inheritance Between Generations

Research Report 2017 - Max Planck Institute for Immunobiology and Epigenetics

Zenk, Fides; Iovino, Nicola
Research has long been concerned with the question of whether epigenetic changes are passed on to the next generation in addition to genetic information. This study shows that an epigenetic modification, H3K27me3, is inherited through the maternal germline and affects gene expression during early embryonic development.

Epigenetic regulation of cell identity

The human body is made up of more than 250 different cell types, all of which have the same genome. One of the explanations for the fact that cells with the same genome can assume completely different identities - a liver cell fulfills completely different tasks than a muscle cell, but both have the same DNA template - is so-called epigenetics. Epigenetic modifications are reversible chemical changes to DNA or histones, which are proteins that package DNA. These chemical changes cause proteins that mediate gene expression to be attracted or repelled. In this way, epigenetic modifications can influence gene expression and define the specific expression patterns of the various cell types.

Each epigenetic modification involves an enzyme that causes modifications to the DNA or the histones, these enzymes are called writer designated. There are other enzymes that remove modifications (eraser) or read (reader) can. The interaction of these three protein classes in each modification ensures that epigenetic modifications are strictly regulated on the one hand and, in contrast to the “rigid” DNA sequence, can also be changed quickly on the other. Epigenetic modifications can therefore change in the course of our lives depending on the adaptation to our environment or our respective lifestyle, and external influences such as stress, illness or diet can influence the epigenetic program of the cells.

Epigenetic inheritance between generations

Epigenetic information differs between individuals, but it is believed that the epigenetic information accumulated during life is erased during the development of sperm and egg cells. This paradigm, in turn, has been challenged again and again in the last few decades by indications that, for example, stress-related chromatin changes can be inherited between generations. Epidemiological studies have revealed an impressive correlation between the diet of parents and the incidence of diabetes or cardiovascular disease in the offspring. Recent studies show examples of epigenetic inheritance in various model organisms, but the underlying molecular mechanisms are still unknown [1-3].

Investigation of early embryonic development

In order to understand the molecular mechanisms of epigenetic inheritance, embryos can serve especially in the course of their early development. The often used microscopic analyzes of various model organisms, however, provide little information about what happens at the molecular level during the fusion of the gametes and the subsequent early cell divisions. An additional hurdle when using early embryos is the consistently small amount of biological material available.

An alternative research approach, namely to find out which role selected enzymes play in epigenetic processes by inactivating the associated genes, unfortunately often leads to defects in the germline, so that no gametes are formed and thus the role of the corresponding gene product cannot be investigated. For these reasons, very little research has been done on early embryonic development at the molecular level.

H3K27me3 is inherited through the maternal germline and regulates gene expression during embryonic genome activation

To explore the role of various chromatin proteins during early embryonic development of Drosophila melanogaster, the fruit fly, to investigate, our laboratory has established various molecular techniques that allow biochemical analyzes to be carried out on very small amounts of biological material. In addition, it is comparatively easy to examine Drosophila with the help of genetic methods. An RNAi-based genetic screening was performed that identified the complex known as PRC2 as an essential factor in early embryonic development. PRC2 catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), and this modification is associated with facultative heterochromatin and transcriptional silencing of genes. It was shown that H3K27me3 is retained on the egg cell's chromatin and is therefore passed on to the embryo through the maternal germ line (Fig. 1; [4]). This modification remains detectable on the embryonic chromatin until the embryonic genome is activated and beyond. With the help of chromatin immunoprecipitation (ChIP) it was possible for the first time to map the genome-wide distribution of H3K27me3 in totipotent, pluripotent and blastoderm embryonic cells. This result is surprising, because it shows that, contrary to previously assumed, early embryonic chromatin is already structured to a certain degree and contains PRC2-regulated domains.

In addition, it could be shown that the maternal inheritance of H3K27me3 is essential for embryonic development. Embryos that develop without H3K27me3 show an accumulation of acetylation at lysine 27. If repressive H3K27me3 domains are replaced with the activating H3K27ac modification, this leads to the incorrect expression of developmental genes with the result that the development program is incorrect and the embryo dies leads (Fig. 2).

Maternal inheritance of H3K27me3 is an evolutionarily conserved mechanism to regulate gene expression during early development [5]. For future research, the question now arises how certain positions in the genome are shaped by H3K27me3 and how they affect the early remodeling Escape processes.

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