Understanding the mechanism of DNA folding

Iconic image

There is no image more iconic in biology than the X-shape of a folded mitotic chromosome. Such chromosomes are made up of DNA that, if it were stretched out, would reach over two meters in total. All this DNA fits inside each tiny cell of our body because it is folded in a precise manner. This folding is all about building loops in the DNA. Careful organisation of these loops is important for many functions inside the cell, as this determines which genes get activated and which remain silent. The switching on and off of genes then determines the behaviour of the cells and the functioning of our bodies. If the DNA is not folded into the right kind of loops, this can lead to disease. Cancer cells for example often have misfolded DNA.

Mysterious loops

In a paper published January 6^th 2020 in Nature, the scientists report their discoveries on how the DNA is folded into such mysterious loops. It was already known that the CTCF protein somehow plays a role in this process. CTCF binds to specific DNA sequences that are found at many spots along chromosomes. Another important regulator is cohesin, a ring-shaped protein that can catch DNA inside its ring. The scientists studied the mechanism by which these important proteins act together to fold the DNA into loops and thereby provide an ordered structure to our chromosomes.

Millions of nucleotides

Such proteins are several orders of magnitude too small to see their structural details using visible light. Dr. Daniel Panne from the University of Leicester and his team used the technique of X-ray crystallography to visualize the detailed atomic makeup of a cohesin component bound to CTCF. This not only revealed the structures of the proteins, but also how they interact and gave vital clues to where the whole mechanism may have originated in evolution. The team of Dr. Benjamin Rowland from the Netherlands Cancer Institute then investigated in cells how this interaction between cohesin and CTCF regulates the structure of DNA. They found that CTCF by binding cohesin manages to fix cohesin on DNA. This then allows cohesin to build loops that connect one CTCF to another CTCF that can lie up to millions of nucleotides (letters that make up the genetic code) further along the DNA.

Every cell in our body contains several meters of DNA that must be folded in exactly the right way. This important process turns out to be entirely dependent on the binding of two proteins within the cell: cohesin (green) and CTCF (purple).

Basic principle throughout evolution

In cancer cells, the part of cohesin that should bind CTCF is often no longer functional. This is likely to cause these cancer cells to misfold their DNA. As a result of this work, it will now become possible to study more precisely how DNA folding contributes to the regulation of genes. Dr. Daniel Panne from the University of Leicester says that "the ability to abolish the interaction between cohesin and CTCF will also facilitate research towards understanding how genome folding contributes to numerous other aspects of genome function." Dr. Benjamin Rowland adds that "it is fascinating to see how this interaction between just a few proteins can determine how all of our DNA is folded inside the cell. It looks like we have encountered a basic principle that controls the folding of DNA throughout evolution."

Li, Y., Haarhuis, J.H.I., Cacciatore, Á.S. et al., The structural basis for cohesin-CTCF-anchored loops. Nature (2020) doi:10.1038/s41586-019-1910-z

Read more about Benjamin Rowland's research:

• How rings and loops organize our DNA
• Research group Gene Regulation

Read also:

• Research into DNA folding awarded €2 million grant