EU researchers explain how sex chromosomes are regulated

UK and German scientists have revealed new information about how sex chromosomes are regulated, they identified the enzyme responsible for helping males make up their hormones shortage, the
work, which is partly EU-funded, is published in the journal Cell.

Chromosomes are long, stringy aggregates of genes that carry heredity information. They are composed of DNA and proteins and are located within the nucleus of our cells.

In every living species, from insects to humans, gender is determined by the presence or absence of the famous X and Y chromosomes. Females have two copies of the X chromosomes, while males
have one X and Y chromosome.

Because females have two copies, they can pump out twice as many proteins from the genes located on the X chromosome as males. To compensate for this, dosage mechanisms are employed to make X
chromosome expression similar in the two sexes. In the Drosophila fruit fly, the X-linked genes in males double their activity, making up for the shortage in proteins.

Research has already identified the mechanism that allows for dosage compensation in male fruit flies, which is called the male-specific lethal (MSL) complex. However, little is known about how
this mechanism actually works.

Enter researchers from the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, and the EMBL-European Bioinformatics Institute (EMBL-EBI) in Hinxton, UK. They have identified
one component in the mechanism, an enzyme called MOF, which stands for ‘males-absent-on-the-first’.

Using genome-wide tilling arrays, the researchers observed how the enzyme, which is found in both sexes, binds differently to chromosomes in males and females.

On autosomes, non-sex chromosomes, and the X chromosome in females, MOF binds mostly to the beginning of a gene where transcription starts. Transcription is the process by which a gene’s DNA is
read to produce messenger RNA. This messenger is then translated into proteins.

On the X chromosome in males, however, MOF binds towards the end of the gene. It is believed that MOF most likely opens up the DNA towards the end of the genes, ensuring 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,’
explains Juanma Vaquerizas of the EMBL-EBI, who contributed to the analysis of the data. ‘It appears that MOF clears the tracks throughout the male X chromosome, while on a female X
obstructions are more likely to occur.’

Because the transcription process can successfully be completed on the male X chromosome, more proteins are produced from the male X chromosome than the female’s two X chromosomes, where
transcription has been blocked. This difference in binding ensures that the amount of proteins produced by the X chromosomes in both sexes is balanced.

MOF is the first enzyme in the MSL complex to behave differently according to 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 homologue. 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,’ says Paul Bertone of the EMBL-EBI.

EU support for the research came from the Epigenome network under the Sixth Framework Programme (FP6), and a Marie Curie Early Stage Research Training Fellowship.

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