During early embryonic development, one of the two X chromosomes in female mammals is randomly inactivated, a process known as X-inactivation. This ensures that males and females have the same dosage of X-linked genes. X-inactivation is a complex process that involves multiple steps, including the coating of the inactive X chromosome with a cloud of RNA molecules known as the X-inactive-specific transcript (XIST).
"XIST is a key player in X-inactivation, but how it spreads along the chromosome to silence genes has remained elusive," said Professor Ana Pombo, who led the research. "We used a combination of supercomputing simulations and experimental data to investigate the mechanisms underlying XIST spreading and chromosome folding during X-inactivation."
The researchers used supercomputers to simulate the interactions between XIST and the DNA of the X chromosome. Their simulations revealed that XIST spreads along the chromosome by forming loops that bring distant regions of the DNA into close proximity. This looping process helps to silence genes by preventing them from being transcribed into RNA.
The researchers also found that XIST spreading is facilitated by the three-dimensional folding of the X chromosome. The X chromosome forms a compact structure that allows XIST to quickly and efficiently reach all regions of the chromosome.
"Our findings provide a new understanding of how the X chromosome folds and deactivates during development," said Pombo. "This could have implications for understanding the mechanisms underlying X-linked genetic disorders, such as Rett syndrome and Fragile X syndrome, which are caused by mutations in genes located on the X chromosome."
The researchers plan to continue their investigations of X-inactivation and chromosome folding using a combination of supercomputer simulations and experimental approaches. They hope that their work will lead to new insights into the mechanisms that control gene expression during development and disease.
