Scientists decode how our genome is functionally compacted
For more than a century, scientists have known that DNA, the genetic material inside our cells, is packaged into structures called chromosomes. These chromosomes contain all the genetic information needed for our cells to function properly. Between cell divisions, these chromosomes are arranged into loops, which play an important role in controlling how the genetic information is used.
Recently, in 2018, a group of researchers was able to see how certain proteins called SMC protein complexes, like condensin and cohesin, help create these loops in the DNA 1. The DNA-binding protein CTCF was found to play a key role in the positioning of loops along the genome. So, CTCF and cohesin were the two proteins that worked together to make DNA loops on chromosomes.
Now, scientists have discovered that DNA tension also plays a major role in determining DNA loops 2. By purifying CTCF and cohesin, scientists were able to reconstitute a DNA loop forming reaction in the lab. The two ends of a DNA molecule were attached to a surface. To this DNA, purified CTCF and cohesin were added. Then, the DNA and the purified proteins were stained with a fluorescent dye. They observed this fluorescent dye as a proxy for the DNA and proteins.
They discovered that DNA tension determined how cohesin and CTCF worked together. Without DNA tension, cohesin often ignored CTCF, even if correctly oriented. However, when the DNA was under more tension, the CTCF acted as a perfect barrier to DNA loop formation by cohesin.
This way, cohesin and CTCF determine the extent of looping of DNA. These DNA loops form topologically associated domains (TADs) that are important for gene regulation in cells. The authors propose that CTCF, cohesin and DNA tension mediated loop formation has implications in TADs and therefore gene regulation.
The authors write,
Our findings reveal that CTCF controls cohesin and therefore genome architecture through multiple modes. Our results will provide the basis for future mechanistic and physiological studies of CTCF’s key functions in gene regulation, recombination and tumorigenesis.
- Mahipal Ganji et al., Real-time imaging of DNA loop extrusion by condensin. Science. 360, 102-105 (2018).
- Iain F. Davidson et al., CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion. Nature. 616, 822-827 (2023).