Deciphering the role of regulatory factors driving epigenetic inheritance of alternative chromatin states

Introduction

Epigenetics, the study of molecules and mechanisms that perpetuate alternative gene activity states in the context of the same DNA sequence, is an exciting field with important epistemological and biomedical implications. However, the molecular mechanisms underlying epigenetic inheritance are still little understood.

Background

Polycomb group proteins are pleiotropic chromatin components that have been suggested to be capable of driving epigenetic inheritance. Their dysregulation leads to cell fate changes and is associated with cancer. Recently, we discovered that a transient decrease in expression of a Polycomb gene can drive the formation of tumors of epigenetic nature, i.e., in the absence of DNA mutations.

Project Goals

The goal of WaddingtonMemory is to decipher how epigenetic components can lead to stable changes in cell fate. Specifically, we will:

1. Aim 1: Identify the molecular steps leading to epigenetic cell fate derailment following transient Polycomb protein depletion in Drosophila. We will perform a time-course study using bulk and single-cell multiomic and imaging approaches in order to dissect the dynamics of cell fate transformation.

2. Aim 2: Identify the Polycomb-targets leading to cell fate dysregulation and decipher their mechanistic role. We will test candidate factors identified in Aim 1 in order to identify those that drive cell fate derailment and to elucidate their mode of action.

3. Aim 3: Test the role of epigenetic inheritance in mammalian cell differentiation. We will analyze the role of epigenetic inheritance in mouse gastruloids, an in vitro system that reflects cell differentiation events typically found in early embryogenesis.

Conclusion

Together, this groundbreaking project will reveal how epigenetic components drive cell fate derailment. It will establish robust paradigms that can be utilized by the scientific community to discriminate between epigenetic inheritance and DNA sequence-mediated cell transformation.