Investigating cohesin’s role in developmental gene regulation using the model organism C. elegans

Abstract

Development of an organism requires tightly controlled gene expression. A disorder of gene regulation is the proposed underlying pathology in a group of developmental disorders termed the “cohesinopathies”. Individuals with cohesinopathies harbour mutations in subunits of cohesin, a highly conserved protein complex that binds DNA to regulate its topology. Although cohesin is essential for chromosome segregation during cell division, due to its role in sister chromatid cohesion (SCC), this process is unaffected in cells from cohesinopathy individuals. More recently, cohesin has been implicated in gene regulation due to its ability to regulate the three-dimensional organisation of DNA fibres. However, investigating this role of cohesin during development is challenging as loss of cohesin results in severe chromosome segregation defects in dividing cells, causing embryonic lethality. Higher eukaryotes have evolved variants of specific cohesin subunits, allowing the formation of different versions of the complex that are known to coexist in the same cell. For example, substitution of the mitotic kleisin subunit (RAD21) by its meiotic counterparts (REC8 and RAD21L) is essential for fertility in all studied organisms. How different kleisins control different functions of cohesin remains poorly understood. The nematode C. elegans, which has clear orthologs of human mitotic (SCC-1) and meiotic (REC-8 and COH-3/4) kleisins, offers an excellent model organism for the study of development. Worms carry a further potential RAD21 ortholog, COH-1, loss of which causes developmental defects. The major goal of this project was to investigate the roles of COH-1 in ensuring normal development. Using multiple experimental approaches, I show that cohesin containing COH-1 is specialised in, and essential for, gene regulation during development, with no apparent role in SCC. This novel cohesin complex therefore provides a unique opportunity to explore the role of cohesin in developmental gene regulation and could provide important knowledge on the causes of cohesinopathies.