The Domino effect

A maternal protein is required to activate the genome of the embryo

After fertilization, the genome of a new organism, created from the genetic material of mother and father, is not active for hours to days, depending on the species. During this time, the genome must be prepared to take over its own transcriptional control, a process called Zygotic Genome Activation (ZGA). Researchers from the Max Planck Institute of Immunobiology and Epigenetics in Freiburg have now been able to identify crucial key molecules responsible for the ZGA in Drosophila melanogaster. Regulated by the enzyme Domino, which is deposited in the egg cell by the mother, the histone variant H2A.Z is an important regulator of gene activation and embryo development.

H2A.Z deposition precedes ZGA. Immunostaining of H2A.Z (top) and DNA in the nucleus (bottom) on embryos showing that H2A.Z already localizes in the nucleus before and during ZGA (pre-ZGA and ZGA, respectively).

In the first hours of life, all animals undergo a fascinating process. Following fertilization, two highly specialized cells, the egg and the sperm, unite to create an entirely new organism with its own genome. Interestingly, the transcription of the new zygotic genome is initially silenced. It cannot produce its own RNA and proteins for hours or sometimes days after fertilization and only survives by relying on maternally supplied RNAs and proteins that have been stockpiled in the egg beforehand.

These same maternal products are also responsible for “preparing” or shaping the zygotic genome to get activated and produce its own RNA and proteins later on. “After fertilization, the chromatin, which is the packaging of the genome, needs to be remodeled to a naïve state. Only this allows later that the single-cell embryo can give rise to the different cell lineages that would ultimately develop into all the different cell types present in the organism. The chromatin remodeling to get everything ready for the takeover of the zygote takes place during the early transcriptional silence,” explains Nicola Iovino, group leader at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg.

The embryo takes over control

This process in embryonic development during which the development comes under the exclusive control of the zygotic genome rather than the maternal genetic material stored in the egg is called Zygotic Genome Activation (ZGA) and involves the simultaneous transcriptional activation of thousands of genes.

The lab of Nicola Iovino wants to understand how the zygotic genome and epigenome is shaped to start its own transcription using the fruit fly Drosophila melanogaster as a model organism. “Specific proteins known as pioneer transcription factors are here essential and act as genome activators. In the fruit fly, a pioneer factor called Zelda is crucial for coordinating Drosophila genome activation. Lack of Zelda stops development and causes embryos to die just before ZGA. However, Zelda only regulates around ten percent of the genes in the early embryo. And this prompted us to question what other mechanisms could exist and how is the rest of the genes regulated,” explains Dafne Ibarra Morales, first author of the study.

H2A.Z as an important regulator during zygote activation

In the newest study, the team found that another enzyme called Domino is essential for shaping chromatin in the very early stages of development. Domino also belongs to the material provided by the mother into the egg. It places a protein called histone variant H2A.Z on the chromatin. “Our data show that H2A.Z deposited by Domino is required for the transcriptional activation of thousands of genes at the onset of the Zygotic Genome Activation. Conversely, without Domino, H2A.Z is decreased on the chromatin, and transcription is severely reduced, resulting in lethality,” says Dafne Ibarra Morales.

Interestingly, most of the genes affected are so-called “housekeeping” genes that are required for the maintenance of basic cellular function such as energy production or cell growth. “Housekeeping” genes are expected to be expressed in all cells of an organism under normal conditions, irrespective of tissue type, developmental stage or cell cycle state. Thus, the histone variant H2A.Z is an important regulator of gene activation and transcription during ZGA in flies, and an essential factor to establish the correct chromatin environment for proper development.

The histone variant H2A.Z is highly conserved from yeast to mammals. Given this evolutionary conservation and the fundamental principles underlying ZGA across animals, the team in Freiburg speculates that histone variants could have similar functions during mammalian embryogenesis. “Future research on histone variants can shed light on the complex process by which chromatin states and transcription factors orchestrate zygotic genome activation not only in flies but also in other animals,” says Nicola Iovino.

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