The human genome contains approximately 3.3 billion base pairs of DNA, though only about 1% of it is known to encode proteins. However, roughly 20% of the genome regulates those protein-coding genes and modify the synthesized product in a variety of different ways. A team of researchers have uncovered how regulatory structures are able to identify and bind RNA to perform those complex regulatory functions. The research was led by Michael Sattler of the Helmholtz Zentrum München and the paper was published in Nature.
In order to express genes to synthesize protein, the necessary DNA or RNA sequence must become transcribed and converted into messenger RNA (mRNA). This mRNA strand is the template by which ribosomes, transfer RNA (tRNA), and several other RNA-binding proteins will come together and translate the code into polypeptide chains, which eventually form proteins. But how do all of those factors know exactly where to go?
Sattler’s lab explored the concept using sex-specific regulatory proteins in fruit flies. Drosophila melanogaster is often used as a model organism in genetic experiments, due to their quick generation times and the fact that they share a majority of the genes known to cause human disease. Drosophila, like humans, have two X chromosomes in females (XX), and just one in males (XY). This means that the females have two sources for the genes encoded on the X chromosomes, while males only have one.
To compensate for only having one X chromosome, males need to increase expression of those genes using the regulatory protein Male-Specific Lethal 2 (msl2). Since females already have two X chromosomes, they do not require an extra boost from msl2. It is incredibly important that the mRNA strand encoding msl2 is identified and silenced in females, or it could have fatal consequences.
To ensure survival, female Drosophila activate a splice factor called Sex-lethal (Sxl). Males do not have active Sxl, so this does not interfere with their genetic expression. Sxl forms a protein complex with Upstream-of-N-Ras (Unr),a post-transcriptional regulatory factor used for dosage compensation in genetic expression. Together, they are able to silence msl2 in females and prevent over expression of genes on the X-chromosome. Expression of msl2 in males, but not females, ensures they will ultimately create the same amount of necessary proteins from genes on the X-chromosomes.
Though this relationship between Sxl and Unr isn’t exactly new, researchers were not entirely sure how Sxl and Unr were able to readily identify the mRNA strand to inhibit msl2. Through the use of crystallography, small angle x-ray, and NMR spectroscopy, the researchers were able to develop a 3D rendering of the complex. They discovered two sections of code that allow Sxl to identify RNA, and Unr’s ability to bind RNA is increased by 1,000 fold when these types of complexes are utilized.
The researchers note that this specific manner of RNA recognition and affinity could be common throughout complex organisms, and could even be the cause of some diseases with protein homologues in mammals.