N6-methyladenosine, or m6A, is a highly abundant base modification which was recently shown to be present in thousands of cellular mRNAs. Many of the functional roles of this mark are carried out by m6A-binding proteins, or ?readers?, which bind m6A residues and contribute to various aspects of mRNA regulation, including mRNA export, stability, and translation. Depletion of the methyltransferase enzymes that catalyze m6A formation has been shown to disrupt stem cell proliferation and differentiation and to lead to developmental defects. In the brain, where m6A is particularly abundant, m6A depletion has been shown to disrupt neurogenesis and cause severe neurodevelopmental abnormalities. However, the mechanisms through which m6A regulates gene expression to control neurodevelopmental processes are poorly understood. In addition, the proteins mediating m6A function in the developing brain have not been explored. Here, we will investigate the function of a previously unknown m6A binding protein during brain development. First, we will uncover the key features that determine m6A binding specificity. Second, we will utilize m6A-depleted neuronal cell lines coupled with transcriptome-wide RNA binding studies to uncover the cellular mRNAs that are targeted by this reader through m6A. Third, we will use a combination of global gene expression profiling and gene targeting approaches to determine how m6A:reader interactions contribute to gene expression changes and neurodevelopment. Collectively, these studies will characterize a novel m6A reader in the brain and will provide important mechanistic insight into how m6A regulates brain development.
Methylation of adenosine residues (m6A) has recently emerged as a pervasive feature of the neuronal transcriptome which plays important roles in regulating neurodevelopment. However, the identity of the proteins that bind m6A in the brain to mediate these effects has not been explored. Here, we will investigate the function of a previously unknown m6A binding protein in the developing brain, which will provide new insights into the mechanism of m6A-mediated gene expression control and potentially identify novel pathways regulating brain development.
