New insights into proteins CTCF and cohesin folding DNA and orchestrating gene activity

A genome consists of all genetic material, DNA, of an organism organized in a 3D structure. The way DNA is organized influences which genes are active and can be ‘read’ by the cell; only readable genes are transcribed into proteins. In other words, DNA organization determines which proteins a cell produces. DNA organization is dynamic and, therefore, so is gene activity.

DNA loops

Every cell in an organism’s body contains the entire genome, which equals to approximately two meters of DNA. To pack all this DNA into the cell’s tiny nucleus, DNA needs to be organized in a compact manner, which can for example be achieved by making DNA loops. Cohesin, a ring-shaped protein, produces these DNA loops through a process called DNA loop extrusion. CTCF is a protein found at the anchors of such loops. Together, cohesin and CTCF largely orchestrate the organization of DNA.

Stem cells

Researchers from the group of Wouter de Laat studied a specific region in the genome of mouse embryonic stem cells to obtain insights into how CTCF and cohesin work together to orchestrate DNA organization. They used a technique called CRISPR-Cas9 to edit the DNA in the region of interest and studied the effects of these edits on DNA looping, CTCF and cohesin recruitment and the activity in nearby genes.

Cohesin and CTCF

The authors report several findings. For example, they conclude that cohesin molecules start migrating and extruding loops from enhancers – DNA sites that can activate gene expression over distance. The extrusion trajectory of cohesin thereby determines which genes the enhancer can activate. In turn, CTCF molecules can change the extrusion trajectory by blocking it. This insulates the genes, preventing them to be activated.

The study, published in Molecular Cell, sheds light on the mechanisms underlying the way in which different DNA elements work together to organize loop extrusion trajectories, orchestrate DNA organization and regulate gene activity.

Publication

Vos, E. S., Valdes-Quezada, C., Huang, Y., Allahyar, A., Verstegen, M. J., Felder, A. K., … & de Laat, W. (2021). Interplay between CTCF boundaries and a super enhancer controls cohesin extrusion trajectories and gene expression. Molecular Cell.