Science for Health
18 June 2012
Researchers at NIMR and their collaborators have identified the gene responsible for X chromosome inactivation in the second largest class of mammals, the metatherians (marsupials). The research is published in Nature.
Most chromosomes and their associated genes are common to males and females but there is one important exception: the sex chromosomes. Males have one X chromosome, while females have two. This means that genes on the X chromosome are present in twice the dose in females as they are in males. Mammals compensate for this imbalance in gene dose through a process called X chromosome inactivation, the silencing of genes on one of the two X chromosomes.
X chromosome inactivation in eutherians (the so-called "placental mammals", such as humans and mice), is controlled by a gene called Xist. However, the gene that controls X chromosome inactivation in the other major class of mammals, the metatherians (or marsupials, such as opossums and wallabies), is unknown and has been the subject of speculation for decades. Recent studies suggest that they use a fundamentally different mechanism to ensure X-dosage compensation. In a previous study James Turner's group noted that in the opossum, the female inactive X chromosome shares common epigenetic features with that of eutherians. It therefore seemed likely that another, unidentified, X-linked RNA initiates X chromosome inactivation in metatherians.
Now James Turner (pictured) and first author Jennifer Grant working with his group, in NIMR's Division of Stem Cell Biology and Developmental Genetics, have identified a metatherian X-linked RNA called Rsx (RNA-on-the-silent X). Working with Greg Elgar, Mike Gilchrist and Willie Taylor from NIMR and collaborators from USA, Australia and New Zealand, they have shown that Rsx exhibits all the properties expected for an RNA involved in X chromosome inactivation.
The researchers studied one South American marsupial (the opossum), and two Australasian marsupials, (the tammar wallaby and brushtail possum). They used RNA FISH and RNA-Seq approaches to analyse the expression of many genes on the marsupial X chromosome. One of the RNAs studied, Rsx, showed an unusual pattern within the nucleus that suggested that it could function in X chromosome inactivation. When the Rsx gene from a marsupial cell was introduced onto a chromosome in a mouse cell, the gene was expressed and resulted in inactivation of the mouse chromosome, showing that Rsx acts to silence genes.
Although not homologous, Rsx and Xist share common features: both are large RNAs enriched in tandem repeats. In female germ cells, where both X chromosomes are active, Rsx expression is silenced, thereby linking Rsx expression to both X-inactivation and reactivation.
X chromosome inactivation is found in most mammals and therefore has important clinical implications. Abnormalities in X chromosome inactivation have been associated with cancer. Normally, X chromosome inactivation is random, affecting either one or the other of the two X chromosomes with equal probability. However sometimes this inactivation becomes skewed, preferentially affecting one of the two X chromosomes, and this has been linked to many conditions, including mental retardation. X chromosome inactivation is therefore of paramount importance to our understanding of many diverse diseases. Now it will be possible to compare the Xist and Rsx genes and delineate exactly how Xist initiates X chromosome inactivation.
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RNA FISH mapping of the novel gene using BAC probes; green BACs give RNA FISH cloud signals, red BACs do not.
Jennifer Grant, Shantha K Mahadevaiah, Pavel Khil, Janine Duckworth, John R McCarrey, John L VandeBerg, Marilyn B. Renfree, Willie Taylor, Greg Elgar, R. Daniel Camerini-Otero, Michael J. Gilchrist and James MA Turner. (2012)
Rsx is a metatherian RNA with Xist-like properties in X-chromosome inactivation
Nature epub ahead of print. Publisher’s abstract
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