Solving a great mystery in the organization of our DNA

Chromosomes are separated into many large topologically associating domains, or TADs. Within each TAD, several genes and the elements that regulate them are packaged together, and they are insulated from those in neighboring TADs. TADs are then further segregated in the three-dimensional space of the nucleus, with TADs containing active genes being compartmentalized away from the ones that do not contain active genes.

HFSP Long-Term Fellow Elphège Nora and HFSP Program Grant holder Job Dekker and colleagues
authored on Tue, 30 May 2017

Findings by Benoit Bruneau (left) and Elphège Nora (right) reshape our understanding of how DNA is organized in cells. Photo: Chris Goodfellow, Gladstone Institutes.

In our new study, we demonstrated that the key to organizing these TADs is a protein called CTCF. Using a recent genetic method to trigger the degradation of targeted proteins, we were able to study the entire genome of mouse embryonic stem cells in the near complete absence of CTCF. Our findings indicate that CTCF is strictly required for insulating TADs from one another, but not for packaging genes within these domains. The two mechanisms are therefore separate and controlled by different factors. We further showed that CTCF and TAD structure are not required for compartmentalization but, rather, that an independent mechanism is responsible for this level of chromosome organization.

Our findings redefine the role of CTCF in gene regulation and provide new insights into the fundamental processes that govern genome organization. With this knowledge, we can now start reevaluating the cause of several diseases, as chromosome organization–including TADs­–is often disrupted in many cancers and involved in developmental defects.

For the full story, read the article from the Gladstone Institutes.

Text by Julie Langelier, Gladstone Institutes

Reference

Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization. Elphège P. Nora, Anton Goloborodko, Anne-Laure Valton, Johan H. Gibcus, Alec Uebersohn, Nezar Abdennur, Job Dekker, Leonid A. Mirny, Benoit G. Bruneau. (2017) Cell. DOI: http://dx.doi.org/10.1016/j.cell.2017.05.004

Link to article