RNA Modification Helps Drosophila Straighten Up and Fly Right

    Absent a certain RNA modification, the flies folded their wings askew, lost their sense of direction, and wafted about listlessly—more listlessly than is ordinary. The RNA modification that the flies lacked is called m⁶A, which refers to the methylation of the nitrogen at position 6 of the adenosine base within messenger RNA (mRNA). The wobbly flies? They were part of a molecularly impaired squadron of Drosophila that had been prepared by scientists at the Institute of Molecular Biology (IMB) and Johannes Gutenberg University Mainz (JGU).

    The scientists, led by IMB researcher Jean-Yves Roignant, Ph.D., suggest that the m⁶A RNA modification is important for brain function. They add that since m⁶A is found in vertebrates as well as in flies, it could also affect brain function in humans.

    The scientists presented their findings December 8 in the journal Nature, in an article entitled, “m⁶A Modulates Neuronal Functions and Sex Determination in Drosophila.” As the title indicates, the scientists didn’t limit their investigation to functions of the nervous system related to locomotion. They also determined that m⁶A is important to fine-tune sex determination, that is, whether a fly develops as male or female.

    “Here we carry out a comprehensive molecular and physiological characterization of the individual components of the methyltransferase complex, as well as of the YTH domain-containing nuclear reader protein in Drosophila melanogaster,” wrote the authors of the Nature article. “We identify the member of the split ends protein family, Spenito, as a novel bona fide subunit of the methyltransferase complex.”

    The study enriches our understanding of a recently discovered phenomenon, that RNA modifications are abundant on mRNA. These modifications are roughly analogous to the kinds of modifications that are found on DNA and give rise to epigenetic effects, changes in transcription that do not require alterations in underlying gene sequences. Similarly, RNA modifications may give rise to epitranscriptomic effects, changes in translation that do not require alterations in the underlying gene transcripts.

    For our bodies to function normally, it is important for genes to be turned on or off in the right cells at the right times. It is already well established that DNA modifications are important to regulate the activity of genes. These molecular marks on the DNA act as signals to the cell machinery that converts the information contained within a gene into a protein, and help determine how a particular gene is regulated. These signals can be added and removed, which changes whether genes are active or inactive.

    Many different modifications have also been identified on RNA, but what they do in vivo was not well understood. m⁶A is the most prevalent of these RNA modifications, and scientists have shown that it can be added and removed in an analogous way to DNA modifications.

    “The discovery that RNA modifications are so abundant on mRNAs was not anticipated until a few years ago,” noted Dr. Roignant. “To my view this is one of the most exciting discoveries in the field in the last 15 years. Our study now sheds light on what they do in living organisms.”

    The present publication is the first comprehensive study investigating the role of all components involved in the biogenesis of the m6A RNA modification in a multicellular organism.

    “We further demonstrate important roles of this complex in neuronal functions and sex determination, and implicate the nuclear YT521-B protein as a main m6A effector in these processes,” the study’s authors continued. “Altogether, our work substantially extends our knowledge of m⁶A biology, demonstrating the crucial functions of this modification in fundamental processes within the context of the whole animal.”

    The current study is likely to prompt additional work in the emerging field of RNA modifications, or epitranscriptomics. “Now we have found that m⁶A is there and that it is important for neuronal functions, we want to understand more about its precise role,” said Tina Lence, a Ph.D. student in the Roignant laboratory at IMB and first author of the Nature paper. “For example, is m⁶A important in all circumstances, or is it more involved in the fine-tuning of gene expression or in response to changes in the environment?”