Predictive Epigenetics: Fusing Theory and Experiment

Project Information

PEP-NET

Grant agreement ID: 813282

DOI

10.3030/813282

Project closed

EC signature date 20 August 2018

Start date 1 November 2018

End date 30 April 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 4 062 699,72

EU contribution

€ 4 062 699,72

Coordinated by

HUMBOLDT-UNIVERSITAET ZU BERLIN
Germany

Periodic Reporting for period 2 - PEP-NET (Predictive Epigenetics: Fusing Theory and Experiment)

Reporting period: 2020-11-01 to 2023-04-30

Summary of the context and overall objectives of the project

Epigenetics research aims to understand how a single genomic DNA sequence can generate and maintain the extraordinary diversity of cell identities and functions that comprise the adult organism. Modifications of DNA and chromatin and the binding of other molecules provide a gene-regulatory layer that modulates gene activity states, so that one genome gives rise to several “epigenomes”.

Epigenetic mechanisms are profoundly implicated in human health and disease. There is virtually no area of human health that is not affected by epigenetics, and pharmaceutical companies are responding rapidly to these discoveries. Despite the importance of epigenetic processes for human health, we are still far from a complete mechanistic understanding of many epigenetic phenomena. A quantitative mechanistic understanding of epigenetic regulation is essential to understand its function in healthy cells and in disease states. Ultimately this knowledge will enable prediction of the effects and side effects of existing therapeutic interventions and the development of new targeted therapies.

The Predictive Epigenetics Network (PEP-NET) is an interdisciplinary research initiative aimed at advancing our understanding of epigenetic regulation through a combination of mathematical modeling and quantitative experiments. The overarching goal of PEP-NET is to develop comprehensive theoretical and experimental descriptions of epigenetic regulation at different scales: single-locus regulation, genome-wide targeting, and 3D genome organization. This initiative also aims to train the next generation of European researchers (PhD students) in interdisciplinary skills, communicate the value of integrating experimentation and theory to a wider audience, and translate research outcomes into commercial and medical applications.

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

Scientific Achievements
Work Package 1: Single-Locus Regulation
WP1 focuses on understanding the molecular mechanisms underlying promoter sensing, epigenetic memory, and switching for various genomic loci. Experimental and modelling work addressed Polycomb/Trithoax Regulation, transcriptional bursting, analog and digital control mechanisms operating at a single target locus, Xist regulation, and the establishment of heterochromatin.

Work Package 2: Genome-Wide Targeting
WP2 aims to uncover the molecular mechanisms guiding epigenetic regulators to specific genomic loci and how they respond to disruptions in chromatin structure. This involves integrating models that consider DNA sequence, chromatin connectivity, and dynamic binding interactions. Researchers within WP2 explored the impact of DNA sequence on epigenetic regulation and investigated transcription factor search mechanisms within complex chromatin structures.

Work Package 3: 3D Genome Organization
WP3 focuses on deciphering the dynamic changes in 3D genome organization and their implications for development, transcriptional regulation, and disease. By applying polymer physics models and innovative imaging techniques, researchers investigated the thermodynamic mechanisms driving chromosomal architecture. We developed models for 3D genome regulation, discovered regulatory binding sites through machine learning approaches, and developed novel protocols and bioinformatic tools for detection of small non coding RNAs, which are the subject of several patent applications.

Training and Career Development
We enrolled 15 ESRs (early stage researchers), 6 of whom have successfully defended their PhDs in 2023, and 6 of whom are currently finishing up (August 2023). Key network events provided interdisciplinary training and transferable skills. The PEP-NET Retreat (Copenhagen, Sept 2022) was a training highlight, being the first in-person event since the pandemic. This event allowed final-year students to present their research, enhance presentation skills, and receive mentoring on career paths and interdisciplinary aspects of epigenetics.

Dissemination
PEP-NET has resulted in 17 publications (Publihsed or available on BioRxiv) and 6 PhD theses so far (August 2023). The final conference of the project took place in Naples in April 2023. This event included scientific talks, communication training sessions, a career orientation workshop, and social activities. The conference agenda was designed to promote interactive scientific exchange and networking among ESRs, PIs, and external speakers.

Public Engagement
The Public Engagement initiative has established social media accounts to share ESR contributions, network events, and various online resources for schools and interested non- scientists. ESRs also engaged with school students through Skype sessions, art projects, and games to foster curiosity and interest in epigenetics. https://itn-pep.net/public-engagement/

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)

Research impact
The combination of quantitative experiments with theoretical models goes beyond what can be achieved with either approach alone. The work we have completed combines globally applicable models with quantitative experiments, and gives unexpected insights into several aspects of epigenetic function. We are thus on the path towards a far broader formalization and a deeper understanding than has previously been possible. Models describing different systems have already begun to uncover unifying principles, and we expect that this trajectory will continue.

Impact on society
In the broader context of the Horizon 2020 Societal Challenges, our research programme is highly relevant to Challenge no. 1 “Health, demographic change and wellbeing,” in particular under the aspects of healthy ageing and personalised medicine. We envisage at least three major socio-economic benefits of PEP-NET projects applying mathematical modelling to epigenetics: Benefits to citizens: we have contributed to education about what epigenetics is and is not and how it impinges on our health and wellbeing. Benefits to healthcare: PEP-NET projects may enable the creation of patient-specific models. Benefits to pharmaceutical industry: PEP-NET projects may enable in-silico trials for the development and assessment of biomedical products, including epigenetic drugs.

Impact on young researchers
PEP-NET has enhanced the career prospects and skills development of a cohort of young researchers by providing comprehensive training in research skills, transferable skills, and industry exposure. PEP-NET fostered original thinking, interdisciplinary collaboration, and entrepreneurial skills. Furthermore, PEP-NET contributes to Europe's innovation capacity by promoting collaboration between academia, industry, and medical fields.

PEP-NET: A highly interconnected network

Epigenetic gene regulation in health and disease

Epigenetics needs mathematics