Unravelling specificity of epi-metabolic regulation in mouse development

Introduction

When the environment of the embryo changes or when development progresses, metabolic reactions are rapidly affected. These alterations to chemical reactions are coupled to epigenetic memory. However, without mechanistic data on how this coupling occurs, it is difficult to understand how normal embryogenesis can proceed.

Project Objectives

This project will elucidate how metabolic changes result in specific epigenetic outcomes and address the function of such regulation. As a model, we will use mouse implantation, a process tightly linked to dramatic alterations to chromatin and transcription.

Findings

We found that this is also associated with extensive metabolic rewiring and that disrupting metabolic flows results in both lineage-specific and mark-specific changes to chromatin. While multiple studies have uncovered that metabolism fuels chromatin modifiers with co-factors, the fundamental biological question of how specificity is achieved remains unanswered.

Hypotheses

Here we will address this challenge by directly testing the three most likely hypotheses:

1. That metabolic reactions shuttle into the nucleus where they specifically fuel chromatin changes.
2. That chromatin-bound metabolic enzymes regulate gene expression.
3. That only specific chromatin modifiers are sensitive to metabolic changes.

Methodology

To address these questions, we will go beyond description as we supplement multi-omic approaches with mechanistic experiments both in vitro and in vivo.

• Firstly, we will use perturbations of nuclear metabolic enzymes and their chromatin binding.
• Secondly, we will implement protein engineering to render chromatin modifiers resistant to the availability of their co-factors.

Expected Outcomes

By uncoupling epi-metabolic regulation, we seek not only to uncover its importance for controlling chromatin states but also the implantation developmental program. This project will form a framework for how future studies can mechanistically unravel intertwined regulatory processes and assess the role of environment and nutrition in early pregnancy.