Cellular identity discovery takes scientists by surprise

Scientists from Trinity College Dublin have led the discovery of new mechanisms involved in establishing cellular identity, a process that ensures the billions of different cells in our bodies do the correct job. This new discovery in stem cells — a result so surprising that the team initially believed it to be an error in the lab — has potential translational impacts in cancer biology and associated targeted treatments.

The research focuses on the workings of Polycomb protein complexes, PRC1 and PRC2, which are studied by Professor Adrian Bracken and his team in Trinity’s School of Genetics and Microbiology. PhD student Ellen Tuck describes these proteins as “strict librarians” inside cells.

“PRC1 and PRC2 block access to certain areas of the genetic library, such that a neuron cell won’t have access to muscle genes, and it doesn’t get confused in its cellular identity,” Tuck said.

A puzzle regarding PRC2 has intrigued the Bracken Lab for years: two forms (PRC2.1 and PRC2.2) exist in the cell, but the Bracken Lab previously showed that the two forms of PRC2 target the same regions of DNA and do the same job. So why do we need two versions? The scientists found that PRC2.1 and PRC2.2 recruit different forms of the PRC1 complex to DNA, thereby finally explaining why two versions are needed.

“This took us by complete surprise,” said Dr Eleanor Glancy, who spearheaded the work together with together with Dr Cheng Wang. “We initially thought there must have been a technical issue with the experiment, but multiple replications confirmed that we had in fact stumbled upon a fascinating new process that reshapes our understanding of the hierarchical workflow of Polycomb complexes. We were dancing around the lab.”

This research by Trinity scientists and their collaborators, published in the journal Molecular Cell, represents a massive contribution to the field of chromatin and epigenetics research. It is also likely to impact cancer biology research, as the genes encoding Polycomb proteins are frequently mutated in cancers.

“My team currently studies the effects of these mutations in childhood brain cancers and adult lymphomas, seeking to understand what biological mechanisms go awry and how we can target these complexes with more effective treatments,” Bracken said. “A firm and comprehensive understanding of the workings of these complexes is critical to figuring out new ways to target them in cancer settings. Therefore, this work led by Dr Glancy and Dr Wang in my lab will be built upon here and by other researchers worldwide to advance our approach to many cancers.”

Image caption: ‘Polycomb Bodies’, courtesy the Bracken Lab.