Epigenetic Reprogramming, Inheritance and Memory: Dissect epigenetic transitions at fertilisation and early embryogenesis

Project Information

EpiRIME

Grant agreement ID: 819941

DOI

10.3030/819941

Project closed

EC signature date 8 February 2019

Start date 1 July 2019

End date 30 June 2024

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 997 500,00

EU contribution

€ 1 997 500,00

Coordinated by

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 4 - EpiRIME (Epigenetic Reprogramming, Inheritance and Memory: Dissect epigenetic transitions at fertilisation and early embryogenesis)

Reporting period: 2024-01-01 to 2024-06-30

Summary of the context and overall objectives of the project

Fertilisation and early embryogenesis are the foundations of life. Despite significant progress in developmental biology, several crucial questions remain unanswered:

1. How are terminally differentiated gametes reprogrammed to totipotency?
2. What is the content and extent of epigenetic information carried from the gametes to the next generation?
3. How is the de novo epigenome established in the early embryo?

The goal of our lab is to break new ground by unravelling the mechanisms that regulate:
- Epigenetic reprogramming of gametes,
- Germline epigenetic inheritance,
- De novo establishment of epigenetic memory.

We use Drosophila early embryo as a model system. These mechanisms are evolutionarily conserved, and thus, our discoveries will pave the way for translational research and novel studies of early embryogenesis that could be applied to vertebrate models.

Key Achievements and Conclusions of the Action:
During the course of this project, we have made significant advancements in understanding the epigenetic mechanisms governing early embryogenesis. Our key achievements include:
- Identification of Maternal Germline-Inherited Histone Modifications
We have successfully identified all the histone modifications inherited through the maternal germline. Our studies have elucidated their physiological functions, providing critical insights into how these modifications influence early developmental processes.
- Role of Histone Acetylation in Zygotic Genome Activation (ZGA)
Our research has highlighted the importance of histone modifications that are established de novo. Specifically, we have focused on histone acetylation and its crucial role in initiating ZGA. Our submitted work demonstrates the significance of these modifications at the single-cell level, showing how they contribute to the regulation of gene expression during early embryogenesis.
- Advancements Leading to Further Research and Leadership
Overall, the ERC Consolidator Grant has been a springboard for my career, leading to my appointment as the Director at the Max Planck Institute (MPI) and the head of the new Department of Developmental Epigenetics. This new role will allow me to continue and expand our research efforts.
- Future Directions: Building on the findings from the Consolidator Grant, the next phase of our research will delve deeper into the role of histone modifications in the phenomenon of transgenerational epigenetic inheritance.

Our goal is to further elucidate the molecular mechanisms of epigenetic inheritance and their impact on development and disease. The findings from this phase will not only enhance our understanding of fundamental biological processes but also have potential applications in regenerative medicine and epigenetic therapies.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the period covered by this ERC, my laboratory made major inroads trying to understand the role of chromatin in controlling the zygotic genome activation and the establishment of the 3D genome organization, as well as identifying all the post-translation modifications that are germline inherited. The results from this research were published in the following manuscripts:

(1) Atinbayeva N, Valent I, Zenk F, Loeser E, Rauer M, Herur S, Quarato P, Pyrowolakis G, Gomez-Auli A, Mittler G, Cecere G, Erhardt S, Tiana G, Zhan Y, Iovino N. Inheritance of H3K9 methylation regulates genome architecture in Drosophila early embryos. EMBO J. 2024 Jul;43(13):2685-2714. doi: 10.1038/s44318-024-00127-z. Epub 2024 Jun 3. PMID: 38831123; PMCID: PMC11217351.

(2) Ciabrelli F, Rabbani L, Cardamone F, Zenk F, Löser E, Schächtle MA, Mazina M, Loubiere V, Iovino N. CBP and Gcn5 drive zygotic genome activation independently of their catalytic activity. Sci Adv. 2023 Apr 21;9(16):eadf2687. doi: 10.1126/sciadv.adf2687. Epub 2023 Apr 21. PMID: 37083536; PMCID: PMC10121174.

(3) Ell MA, Schiele MA, Iovino N, Domschke K. Epigenetics of Fear, Anxiety and Stress - Focus on Histone Modifications. Curr Neuropharmacol. 2024;22(5):843-865. doi: 10.2174/1570159X21666230322154158. PMID: 36946487; PMCID: PMC10845084.

(4) Ibarra-Morales D, Rauer M, Quarato P, Rabbani L, Zenk F, Schulte-Sasse M, Cardamone F, Gomez-Auli A, Cecere G, Iovino N. Histone variant H2A.Z regulates zygotic genome activation. Nat Commun. 2021 Dec 1;12(1):7002. doi: 10.1038/s41467-021-27125-7. PMID: 34853314; PMCID: PMC8636486.

(5) Zenk F, Zhan Y, Kos P, Löser E, Atinbayeva N, Schächtle M, Tiana G, Giorgetti L, Iovino N. HP1 drives de novo 3D genome reorganization in early Drosophila embryos. Nature. 2021 May;593(7858):289-293. doi: 10.1038/s41586-021-03460-z. Epub 2021 Apr 14. PMID: 33854237; PMCID: PMC8116211.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The ERC Consolidator Grant has enabled us to make groundbreaking discoveries in the field of developmental epigenetics. We have identified key histone modifications inherited through the maternal germline and elucidated their roles in early embryogenesis. These achievements set the stage for exploring the mechanisms of transgenerational epigenetic inheritance in greater detail. Our work continues to push the boundaries of developmental biology and epigenetics, with the ultimate aim of translating these findings into broader biological and medical applications.

Is there Epigenetic inheritance via the Germline?