Cellular Identity Discovery Shows Potential to Impact Cancer Therapies

A scientific team led by researchers at Trinity College Dublin reports 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 stem cell discovery—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, according to the researchers, who published their work “PRC2.1- and PRC2.2-specific accessory proteins drive recruitment of different forms of canonical PRC1” in Molecular Cell.

“Polycomb repressive complex 2 (PRC2) mediates H3K27me3 deposition, which is thought to recruit canonical PRC1 (cPRC1) via chromodomain-containing CBX proteins to promote stable repression of developmental genes. PRC2 forms two major subcomplexes, PRC2.1 and PRC2.2, but their specific roles remain unclear,” write the journal article authors.

“Through genetic knockout (KO) and replacement of PRC2 subcomplex-specific subunits in naïve and primed pluripotent cells, we uncover distinct roles for PRC2.1 and PRC2.2 in mediating the recruitment of different forms of cPRC1. PRC2.1 catalyzes the majority of H3K27me3 at Polycomb target genes and is sufficient to promote recruitment of CBX2/4-cPRC1 but not CBX7-cPRC1. Conversely, while PRC2.2 is poor at catalyzing H3K27me3, we find that its accessory protein JARID2 is essential for recruitment of CBX7-cPRC1 and the consequent 3D chromatin interactions at Polycomb target genes.

“We therefore define distinct contributions of PRC2.1- and PRC2.2-specific accessory proteins to Polycomb-mediated repression and uncover a new mechanism for cPRC1 recruitment.”

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

Intriguing puzzle

A puzzle regarding PRC2 has intrigued the Bracken lab and other scientists in the field for years: two forms (PRC2.1 and PRC2.2) exist in the cell but the 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 new finding takes a step towards answering this conundrum, as the team 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. 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,” says Eleanor Glancy, PhD, recalling the evening the team finally realized what the data were telling them.

The team believes their study represents a major contribution to chromatin and epigenetics research and has further impact in 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,” explains Bracken. “A firm and comprehensive understanding of the workings of these complexes is critical to figuring out new ways to target them in cancer settings.”