Decoding the Epitranscriptome: Reader Proteins Tailoring Regulatory Functions of mRNA Modifications

Eukaryotic cells utilize a wide range of mechanisms to regulate gene expression, generating divergent expression profiles for distinct cellular functions. In addition to the primary sequences of DNA and RNA that code for protein, modifications on the nucleic acids serve as additional "codes" for precise control of gene product level. "Epigenetics" studies how DNA and histone modifications alter gene expression without changing DNA sequences. As an analogy, a newly-emerging field called "epitranscriptomics" focuses on chemical marks on RNA species. N6-methyladenosine (m6A) is the most abundant internal modification on eukaryotic messenger RNA (mRNA) and impacts various aspects of RNA function and metabolism. m6A methylation can be recognized by assorted binding proteins called "readers", and each reader may group a subset of m6A-modified transcripts for particular downstream processing. In this thesis, we report the translational promotion function of a reader YT521-B homology domain family 3 (YTHDF3). We then take the physiological example of learning and memory in mice to demonstrate the biological significance of m6A-mediated translational regulation through another reader YTHDF1. We also report the discovery and characterization of additional classes of m6A readers. Studies of readers proteins may provide valuable mechanistic insights into the multifunctionality as well as the specificity of functions of RNA modifications, not only in proper cell fate transition but also in optimal cellular response.