Dynamic interplay of Polycomb complexes in establishing and maintaining cellular memory

Epigenetic mechanisms orchestrate the development of complex organisms and play a role in many human diseases and medical interventions – neurodegeneration, cancer, diabetes and cardiovascular diseases, AIDS, stem cells therapy and reprogramming.

My project aims to elucidate the dynamic interplay of Polycomb group (PcG) proteins in establishing and maintaining cell identity.

Two major PcG complexes, PRC1 and PRC2, cooperate in the repression of target genes catalyzing histone H2A ubiquitination and H3K27 trimethylation, respectively.

Their mode of action is highly debated, partly due to the lack of suitable methods for studying their biochemistry in cellulo.

Here, I will combine a dynamic labelling protocol (RAPID)  with quantitative ChIP-Seq, and mass spectrometry to understand Polycomb mechanism.

First, I will elucidate the dynamics of PcG proteins and their marks genome-wide, their mode of initial recruitment and propagation through cell cycle.

I will use genetic manipulation in combination with dynamic labeling and mathematical modeling to detail the molecular mechanisms.

Second, I will capture quantitative epigenomic maps along differentiation trajectories from naïve mESC, revealing earliest steps in lineage commitment, including the role of X inactivation.

My research program will provide a paradigm for synthetic biology enabling biochemistry in the living cell and shed light into the mechanism of cellular memory and epigenetic lineage specification.