How females shut off their second X chromosome?

The quest to understand all the molecular mechanisms behind X-inactivation.

In mammals, males and females vary genetically in their sex chromosomes—XX in females and XY in guys. This prompts 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 maintain this imbalance, which has been appeared to prompt early embryonic lethality, female embryos shut down the expression of genes on one of their two X chromosomes.

Scientists did not fully understand how genes become silenced on the X chromosome, although a molecule called Xist is known to initiate the process. 

Xist is a long non-coding RNA—a type of molecule created using the cell’s DNA as a template, but one which doesn’t carry instructions for making a protein. Xist coats the chromosome from which it is expressed and induces silencing.

EMBL/Curie Ph.D. student François Dossin said“The exact molecular mechanisms by which Xist mediates gene silencing have been a mystery for decades.”

In the new study, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg and Institut Curie in Paris have shown that the protein SPEN plays a crucial role in the process of X-chromosome inactivation, where female mammalian embryos silence gene expression on one of their two X chromosomes.

The study reveals how SPEN targets and silences active genes on the X chromosome, providing critical new insights into the molecular basis of X-inactivation.

Knowing SPEN is a crucial player in X-chromosome inactivation, scientists studied how SPEN induce gene silencing in mouse embryos and embryonic stem cells.

To comprehend SPEN’s action, scientists reduced its concentration in embryonic stem cells. But X-inactivation did not happen. They also found where SPEN binds on the X chromosome to do its job. As soon as it is expressed, Xist mobilizes and binds SPEN, which accumulates along the X chromosome. SPEN then interacts with the regulatory regions of active genes. As soon as gene silencing occurs, SPEN disengages. Genes then remain inactive for the rest of the cell’s lifetime.

François Dossin said, “We dissected SPEN’s role during X-chromosome inactivation using a wide array of classical and cutting-edge approaches.”

Scientists found that a specific domain of SPEN called SPOC played the lead role in gene silencing. It represses the transcription of DNA into RNA and interacts with several proteins involved in RNA synthesis, as well as chromatin remodeling and modification.

Edith Heard, Director General of EMBL, said, “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.”

This landmark research is published in Nature.

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