DNA Editing Shortened One Chromosome End in a Cell Line

DNA Editing Shortened One Chromosome End in a Cell Line

On September 7, Nature Communications published a study examining how the two copies of the same chromosome end can differ in length. The authors tracked the inheritance of unusual sequences within telomeres across families, then removed one such region using targeted DNA editing. In cultured cells, the edited chromosome end became shorter.

Telomeres are repetitive DNA regions at the ends of chromosomes. Conventional measurements report the average length of all telomeres in a sample, which can obscure differences between two inherited copies of the same chromosome end.

A 2023 study showed how individual telomeres could be measured. In the new study, the researchers read the sequence of each telomere precisely and matched it to longer adjacent DNA fragments. This allowed them to assign the sequence and length to a specific copy of a chromosome end. In six families, the authors found that each chromosome end was inherited together with its sequence pattern. The standard DNA repeats, written as TTAGGG, were interspersed with altered repeats and short insertions. These variant sequences, called TVS, help distinguish telomeres on chromosome copies inherited from the mother and the father.

The causal test was conducted in HCT116, a cancer cell line in which the enzyme telomerase maintains telomere length. In this cell line, the association between the amount of TVS and telomere length was particularly strong. Using CRISPR, a tool for targeted DNA editing, the researchers removed a region containing TVS from one of the two copies of the long arm end of chromosome 1. After more than 50 cell divisions, cells from four clones carried a telomere that was 645–900 base pairs shorter than in the original cell line. The comparison was adjusted for the average length of all telomeres in each clone.

A second edited region produced little change in the TVS pattern and no detectable shortening. The unedited copy of the same chromosome end remained close to its original length. Together, these comparisons link the shortening to the larger change in TVS on one copy of the chromosome end.

The family measurements established that the sequence pattern was inherited, while the intervention tested its effect on a specific chromosome copy. In this cell system, a substantial change in TVS was accompanied by persistent shortening of the corresponding telomere.