Understanding of How Females Inherit Traits May Shed Light on Fragile X, Rett Syndromes, Study Says

New understanding of the genetic mechanisms involved in female inheritance and X chromosome silencing may help shed light on disorders arising from defects in the X chromosome, including fragile X syndrome and Rett syndrome, a study reports.

Findings of the study, “Developmental Xist induction is mediated by enhanced splicing,” were published in the journal Nucleic Acids Research.

All females have two X chromosomes, while males only have one, along with an unmatched Y chromosome. However, despite having two X chromosomes, female cells only have one chromosome active at a time. The other chromosome is permanently shut down early on during embryonic development.

“[X chromosome inactivation] ensures that females express similar dosages of X chromosome gene products as males do,” Sika Zheng, PhD, an assistant professor of biomedical sciences at the University of California Riverside School of Medicine and corresponding author of the study, said in a press release. “This inactivation ensures, too, that, like males, females have a balanced expression between the X chromosome and autosomes — chromosomes that are not sex chromosomes.”

So far, the mechanisms behind the process of shutting down one of the two X chromosomes, known as X chromosome inactivation (XCI), have remained shrouded in mystery.

But now a team of researchers led by Zheng have found that X chromosome inactivation involves RNA splicing in a gene called XIST that is only found in the female’s inactive X chromosome.

RNA splicing is the process by which introns (the gene sequence that does not code for a protein) are removed to create a final messenger RNA molecule containing the gene sequence that provides instructions to make proteins.

Using embryonic stem cells from female mice, the scientists found that an RNA splicing event takes place in the XIST gene before X chromosome inactivation in the particular X chromosome selected for inactivation, but not in the one that remains active. Based on these findings, they now believe that RNA splicing in XIST could be the trigger to initiate X chromosome inactivation.

Embryonic stem cells are derived from undifferentiated cells found in embryos and are able to grow, or differentiate, into any type of cell of the adult body.

Results showed that while embryonic stem cells remained in an undifferentiated state (two X chromosomes still active), XIST was not spliced and remained inactive. However, once embryonic stem cells started to differentiate, XIST was spliced and became functional, triggering the process of X chromosome inactivation.

According to the researchers, understanding the genetic mechanisms controlling female inheritance and X chromosome inactivation may be important to grasp and counteract some disorders caused by genetic mutations in the X chromosome, such as fragile X syndrome and Rett syndrome.

“The splicing mechanism is fundamental to understanding trait inheritance in females,” Zheng said. “If we could manipulate which X chromosome to inactivate through splicing, we might be able to alter females’ expression of their genetic traits and their susceptibility to diseases without altering their genomes. Regulating XIST transcription [DNA conversion into RNA, the template for the production of a protein] has been at the center of this research field for a long time. Our discovery should draw scientists’ attention to splicing.”