Researchers have begun to understand the molecular mechanism behind the silencing of one of the X chromosome in female mammalian embryos.
The team at the European Molecular Biology Laboratory (EMBL) in Heidelberg and Institut Curie in Paris have shown that the protein SPEN targets and silences active genes on the X chromosome, providing new insights into the molecular basis of X-inactivation.
“We dissected SPEN’s role during X-chromosome inactivation using a wide array of classical and cutting-edge approaches,” said EMBL/Curie PhD student François Dossin.
In mammals, males and females differ genetically in their sex chromosomes – XX in females and XY in males. This leads to a potential imbalance, as more than a thousand genes on the X chromosome would be expressed in a double dose in females compared to males. To avoid this imbalance, which has been shown to lead to early embryonic lethality, female embryos shut down the expression of genes on one of their two X chromosomes.
There is no full understanding how genes actually become silenced on the X chromosome, although a long non-coding RNA called Xist is known to initiate the process. Xist coats the chromosome from which it is expressed and induces silencing.
“Theexactmolecular mechanisms by which Xist mediates gene silencing havebeen a mystery for decades,” said Dossin.
In the new study, published in Nature, the team identified how SPEN – a key player in X-chromosome inactivation – functions to induce gene silencing in mouse embryos and embryonic stem cells. This study provides some of the first detailed molecular insights into X-inactivation since its discovery in 1961.
The quest to understand all the molecular mechanisms behind X-inactivation has only just begun. “We found that SPEN interacts with several pathways linked to gene silencing. Given that SPEN accounts for nearly all the silencing during X-inactivation, the next question to address is how much each of those pathways contributes to gene silencing,” explained Edith Heard, Director General of EMBL.