Study reveals how males make up for their X chromosome shortage

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Washington, May 30 : Uncovering new insights into how sex chromosomes are regulated, researchers at European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and the EMBL-European Bioinformatics Institute (EMBL-EBI) in Hinxton, UK, have found that an enzyme, called MOF, binds differently to male and female sex chromosomes and thus helps males to make up for their X chromosome shortage.

This, chromatin modifying enzyme aids in compensating for the fact that males have only one copy of the sex chromosome X, while females have two, by distinguishing between male and female sex chromosomes in fruit flies and binding to different locations on the male and female X chromosome. In fact, this evolutionarily conserved enzyme is also found in humans.

We know that in most of the organisms, females have two copies of the X chromosome while males have one X and one Y, which implies that females produce twice as many proteins from the genes carried on the X chromosome as males.

But fruit flies cover up for the sex chromosome difference by doubling the activity of genes on the X chromosome in males, a vital process called dosage compensation. It's already known that a molecular machine called the MSL complex facilitates dosage compensation in flies, but the mechanism by which it accomplishes its function is still unknown.

Researchers from the lab of Asifa Akhtar at EMBL and the groups of Nick Luscombe and Paul Bertone at EMBL-EBI have now revealed how MOF, a component of the MSL complex, ensures that the activity of only male X chromosome genes is progressed. MOF relaxes the structure of chromatin - tightly packaged DNA, to facilitate the transcription machinery to access genes on the DNA. We were very surprised to find MOF bound not only to the X chromosome in males, but also to all the other chromosomes in the nucleus. This suggests the enzyme as a universal regulator of transcription that has evolved to play a specific role in dosage compensation," said Akhtar.

On close examination, it is revealed that MOF binds differently to chromosomes from males and females. MOF binds on autosomes, chromosomes that are not involved in determining sex, and the X chromosome in females, mainly to the beginning of a gene where transcription starts.

However, in case of the X chromosome in males, MOF binds also towards the end of the gene. Usually, MOF opens up the DNA towards the end of the genes and ensures that transcription is completed successfully.

"One can imagine the transcriptional machinery moving along the DNA like a train on a railway track. When the tracks are blocked the train could derail, resulting in incomplete transcription. It appears that MOF clears the tracks throughout the male X chromosome, while on a female X obstructions are more likely to occur," explained Juanma Vaquerizas of Luscombe's lab, who contributed to the analysis of Akhtar's data.

It was revealed that more complete transcription causes more proteins to be produced from the single X chromosome in males than from either of the two X chromosomes in females, which in turn balances out their excess. MOF is the first enzyme in the MSL complex to behave differently depending on whether the target gene is located on the sex chromosome versus other chromosomes in males.

"MOF is conserved across species and also has a human homolog. Since the mechanism of dosage compensation is radically different in mammals, it will be very interesting to discover what functional role this enzyme might play in that context," said Bertone.

The study is published in the current issue of the journal Cell.

ANI

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