Development of novel single cell multi-omics methods to uncover regulators of cell type specific epigenetic states.

Introduction

Although all cells of an organism share the same genetic information, they selectively access this information in a cell type- and context-dependent manner. Epigenetic mechanisms, such as post-translational histone modifications (PTHMs), have been identified as central regulators of Transcription Factor-DNA interactions.

Cell Differentiation and PTHMs

During cell differentiation, the distribution of PTHMs is modulated to enable the new cell state. Most of the protein complexes that position (writer) and remove (eraser) PTHMs have been identified, but we still do not understand how these proteins are recruited to the genome and thereby dictate the specific genomic distribution of PTHMs.

Challenges in Identifying Targeting Factors

Previous studies were unable to identify these targeting factors as they only interact with a fraction of writer complexes at a time and likely form transient interactions. Thus, new experimental approaches are needed to identify these proteins that are directing localized epigenetic changes.

Project Overview

In scEpiTarget, I will develop novel single-cell methods to identify the key factors that determine cell-type specific PTHM deposition. I will use the identified regulators to re-target PTHMs and evaluate their impact on cell fate decisions in state-of-the-art cell differentiation systems.

Technological Breakthrough

Recently, I made a technological breakthrough by developing a method that allows the simultaneous measurement of histone modifications and total RNA in single cells. Together with my background in genetic screening and chromatin biology, this will enable me to reach scEpiTarget’s objectives.

Broader Implications

The proposed techniques are transferable to study any protein:DNA interaction, making them highly valuable for the research community.

Importance of Epigenetic Pathways

Epigenetic pathways are essential for multi-cellular life from the beginning of embryonic development until their mis-regulation during aging. The identification of factors regulating PTHM distribution will lead to a better understanding of their function and how they can be therapeutically influenced during pathogenesis.