Kate D. Meyer
Epitranscriptomic Control of Local Gene Expression in the Brain
The translation of mRNAs residing in unique subcellular loci is an important mechanism through which cells achieve spatial and temporal control of gene expression. Such local translation events are particularly important in neurons, in which distal compartments such as synapses may be located far away from the cell body. Local protein synthesis in neurons has been shown to play important roles in neurophysiological processes, such as mediating synaptic potentiation events which underlie learning and memory. Although recent technological advances have yielded unprecedented insights into the mRNAs and proteins that reside in distal compartments, we lack a clear mechanistic understanding of how resident mRNAs are selected for local translation in neurons.
Recently, a major advance in our understanding of RNA regulation in cells has come from the discovery that mRNA modifications are a pervasive feature of the transcriptome. One particularly abundant mRNA modification occurs when adenosine residues are methylated to form a modified base called m6A. Although studies done in the1970s were the first to demonstrate the existence of m6A, recent next generation sequencing-based methods have enabled transcriptome-wide detection of this mark and have revealed that thousands of cellular mRNAs contain m6A residues. Furthermore, m6A is particularly abundant within the brain, and emerging evidence indicates that m6A plays important roles in neurodevelopment and brain function. However, our understanding of how m6A contributes to local gene expression changes at the synapse and in response to synaptic activity remains limited. My laboratory seeks to elucidate the mechanisms through which m6A-mediated changes in mRNA localization and local translation at the synapse contribute to neuron function. We approach this question using a combination of biochemical techniques, global transcriptome and proteome mapping strategies, and cell biological methods. Our major goal is to uncover the mechanisms through which m6A influences local gene expression in neurons and to advance our understanding of the fundamental features of gene expression control within the brain.