Single-cell epigenomics in the central nervous system

Profiling of gene expression at the single-cell resolution has been revolutionary for our understanding of developmental processes and disease heterogeneity.

However, to fully discern the underlying regulatory mechanisms, we need to investigate epigenetic modalities at the same resolution.

The aim of this project is to develop methods to profile multiple histone modifications in single cells and to investigate enhancer dynamics during development and disease at the single-cell level.We have recently developed a method (scCUT&Tag) to profile histone modifications at the single cell resolution.

Here, I propose to further improve the technology to profile multiple histone modifications and open chromatin in the same cell.

This would let us to in-depth study epigenetic mechanisms of regulation of gene expression and interplay between various histone modifications and chromatin opening.

Then, I would like to apply scCUT&Tag and its multimodal versions in the study of embryonic development of the central nervous system in human and in cancer.

We will then use the single-cell resolution histone profiles to identify the most dynamically regulated enhancers/promoters and investigate the function of SNPs that overlap them using complementary methods such as enhancer reporter assays (STARR-seq) and CRISPR-Cas9. Together we will dissect the enhancer activity during human development and disease at unprecedented resolution.