m6A mRNA methylation - understanding an essential mechanism adjusting gene expression during development and differentiation

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The information for life is encoded in the DNA of the genes harbored on our chromosomes. The DNA in a chromosome is a very long chain consisting of four different nucleotides: G, A, C and T. For most genes this code is then converted via a messenger RNA intermediate (mRNA) into a chain of amino acids called proteins, which fulfill a function; for example an enzymatic reaction to generate energy from the nutrients we eat to allow for the electrical communication among neurons in our brain. Although proteins consist of long uninterrupted chains of amino acids, this is not the case for the genetic code in the DNA. The coding sequence of almost all genes in the DNA termed exons is interrupted by non-coding sequences called introns. When the DNA sequence is transcribed into a complementary pre-mRNA the intervening intronic sequences need to be spliced out to make the mature mRNA. Thus, correct splicing of pre-mRNAs is a very important process, but the sequences directing splicing of small exons, which are generally hidden in very large introns are very short and appear fuzzy to us humans. Nevertheless the splicosome cuts introns out very accurately. But there is much more to splicing than simply producing a "correct" transcript, because the exon content can be varied by a process called alternative splicing. Strikingly, it is the amount of alternative splicing in our genes, and not the number of genes that distinguishes us from simpler organisms. These differences are most prominently manifested in the genes that are expressed in our most complex organ, the brain.Intriguingly, the sequence of RNA does not just consist of four nucleotides, because many can be modified by addition of small chemical groups. The most prominent modification in mRNA is methylation of adenosines (m6A), which is required for viability of mice and plants. We recently discovered that mutant Drosophila lacking the m6A modification are viable, although with neurological and metabolic defects. We further discovered that female viability is compromised. Using sensitive genetic interactions possible due the viability of these mutants allowed us then to reveal a fundamental role of m6A in alternative splicing of the master regulator of sex determination Sex lethal (Sxl) in the fruit fly Drosophila. Sxl has an additional role and is required to adjust gene expression of the unequal numbers of X-chromosomes between males and female; a process called dosage compensation that is most affected in m6A devoid females. Hence, we now have the ideal animal model to address the very fundamental questions about how this enigmatic modification adjusts expression of genes. Our preliminary data indicate that the m6A modification has important functions in early embryogenesis, when sexual fate is established and the genome is reprogrammed for later development. Accordingly, we will globally map m6A sites in early embryogenesis and use the genetically sensitive Sxl paradigm to ask the very fundamental question how the dynamics of m6A levels are used to adjust gene expression during development and differentiation of cells. These studies are essential to understand the vital function of the m6A modification in the regulation of gene expression and how its aberrant regulation can lead to neurological and metabolic defects in humans, or can be exploited to interfere with viral replication such as in Zika virus.