Study Uncovers Protein’s Role in Maintaining Pluripotency

Understanding of the genome’s spatial arrangement can provide researchers with valuable insight into general biology and how certain diseases emerge. A study published today in Cell Reports provides details on a protein complex called cohesin. Known for its role in chromosome segregation in dividing cells, recent evidence suggests it also plays a role in 3D genome architecture and regulation of essential cellular processes. The findings reveal how cohesin acts to maintain pluripotency in embryonic stem cells and may also be significant for development of disease treatments as cohesin mutations have been identified in some cancers and rare diseases.

There are two variants of cohesins—SA1 or SA2. Mutations in the gene that encodes SA2 show high mutation rates in some types of cancer, but mutation rates of SA1 are much lower. A 2018 study had previously revealed the distinct role of each of these two variants in human epithelial cells.

In the current study, researchers at the Chromosome Dynamics Group at the Spanish National Cancer Research Centre (CNIO) took a deeper look into the two variants using mouse embryonic stem cells, which operate similarly to human embryonic stem cells. Not only were they able to confirm the findings seen in human epithelial cells, but they were also able to show how cohesin-SA1 contributes to differentiation of distinct regions of the genome and how cohesin-SA2 maintains pluripotency in cells through 3D organization of Polycomb domains.

Polycomb domains are 3D genome structures only present in embryonic stem cells. These domains act to repress genes that would otherwise help initiate cell differentiation. The new study revealed that cohesin-SA2 retains one of the proteins within the Polycomb complex. When cohesin-SA2 decreases in cells, Polycomb protein levels in chromatin decrease causing the chromosomes to loosen. Consequently, expression of tissue-specific genes is not properly silenced so stem cells lose their pluripotency and can no longer work properly.

Further researcher is needed to understand the link between cohesin and Polycomb complexes in differentiated cells and how this relates to emergence of cancer and other disorders like cohesinopathies.

Image: Two mouse embryonic stem cells in which two Polycomb regions from different chromosomes (HoxC, green; HoxD, red) appear next to each other (arrows). Cohesin-SA2 promotes this type of contacts between distant Polycomb regions, while cohesin-SA1 does the opposite. Image courtesy of Molecular Cytogenetics Unit. CNIO.