The project is spearheaded by our wonderful research associate Christian Much along with a dream team - grad student Sandy Rajkumar, postdoc Liming Chen, technician John Cohen and our amazing collaborator Dr. Geoff Pitt @geoffrey-pitt.bsky.social & Aravind Gade in his lab @weillcornell.bsky.social.

We also dived into the three mutually exclusive PRC2.1 complexes. Surprisingly, PHF19 antagonizes the role of MTF2 on regulating PRC2 occupancy and H3K27me3 deposition. MTF2 loss-of-function mutants also phenocopies the cardiomyocyte differentiation phenotype of the loss of PRC2.1 line.

PRC2.1 and PRC2.2 exhibits opposing function in cardiomyocyte differentiation, potentially through their specificity on key transcription factor and ion channel genes. Interestingly, loss of PRC2.1 accelerates differentiation and increases spontaneous action potential frequency.

Loss of PRC2.1 or PRC2.2 in hPSCs by separation-of-function mutants led to loss of H3K27me3 in a gene-specific manner. For example, the H3K27me3 peaks at BARHL1 and ARV1 are specifically deposited by PRC2.1 and PRC2.2, respectively. This specificity is observed genome wide.

It provides compelling evidence that the PRC2 subcomplexes act non-redundantly and regulate lineage-specific gene expression through distinct macromolecular interactions. Thanks to our collaborator and neighbor Dr. Geoff Pitt @geoffrey-pitt.bsky.social !

We use a human pluripotent stem cell model and a serial of CRISPR-mediated separation‐of‐function mutants to reveal that distinct Polycomb Repressive Complex 2 (PRC2) subcomplexes (PRC2.1 and PRC2.2) differentially deposit H3K27me3 and oppositely affect cardiomyocyte differentiation.

Thanks for the recognition and kind words, Matthias!