Understanding of How Females Inherit Traits May Hold Key to Treatment of X-linked Disorders
Researchers have discovered the genetic mechanisms involved in female inheritance and X chromosome silencing. This process, known as X chromosome inactivation, can potentially be manipulated for the treatment of disorders arising from defects in the X chromosome, including fragile X syndrome and Rett syndrome, a study reports.
The study, “Developmental Xist induction is mediated by enhanced splicing,” was published in the journal Nucleic Acids Research.
There are two types of sex chromosomes in mammals — X and Y. Males have one X chromosome, which they inherit from the mother, and a Y chromosome, which they inherit from the father. Females, on the other hand, have two X chromosomes, one from the mother and one from the father.
In order to even out the expression of genes on the X chromosome, females undergo a process called X chromosome inactivation (XCI), in which one of two X chromosomes is silenced. Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein.
“[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.”
However, so far, the mechanisms behind X chromosome inactivation have remained unknown.
Now, researchers led by Zheng have found that X chromosome inactivation involves RNA splicing in a gene called XIST that is only found in a 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 team found that an RNA splicing event takes place in the XIST gene before X chromosome inactivation in one of the X chromosomes. As such, RNA splicing in XIST could be the trigger to initiate X chromosome inactivation.
Of note, 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.
While embryonic stem cells remained in an undifferentiated state (two X chromosomes still active), XIST was not spliced and remained inactive. However, once these cells began to differentiate, XIST was spliced and became functional, triggering the process of X chromosome inactivation.
“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.”
Understanding these genetic mechanisms could allow researchers to understand and counteract some disorders caused by genetic mutations in the X chromosome, including Rett syndrome.