EPIGENETIC MEMORY BY COMMUNICATION ACROSS CHROMOSOME SCALES

Introduction

The ability of cells to specialize and maintain their identity through multiple cell divisions is critical for development, tissue renewal, and disease avoidance. A key frontier is therefore to understand how genome organization and function is inherited to daughter cells.

Project Overview

EPICHS targets a new paradigm for how epigenetic information is propagated, in which communication between the 2D epigenome and 3D genome organization maintains cellular identity. Inheritance of epigenetic states involves the copying of modifications on DNA and histones in cis on replicated DNA.

Challenges in Current Models

However, this model lacks a spatial dimension, integrating that similar chromatin types separate spatially in the nucleus and replicate in a coordinated fashion. DNA replication severely disrupts the 2D epigenome, but it is unknown how replication locally impacts 3D organization and how spatial context shapes replication of the epigenome.

Research Objectives

EPICHS will interrogate chromosome replication across scales. We will develop new technology to address the interplay between 2D and 3D epigenome in epigenetic inheritance across replication. We will combine these technologies with machine learning, proteomics, and fast-acting degrons to manipulate chromatin replication.

Functional Exploration

Functionally, we will explore replication-induced 2D/3D dynamics and inheritance mechanisms in the regulation of transcription and stem cell plasticity. Together, this will:

1. Provide the first knowledge of interdependencies and directionality in the propagation of 2D and 3D organization.
2. Reveal functions of DNA replication-induced plasticity in cell fate transitions.
3. Unveil spatio-temporal epigenetic mechanisms and their synergy with cis-based memory in maintaining cell identity.