Visualizing and understanding RNA modifications in brain function by in situ sequencing
Controlling gene expression through DNA transcription in the cell nucleus is typically the dominant mechanism to shape cell type and state. However, the gene regulation scheme is more complicated in the brain. The basic unit of the brain is a neuronal cell (neuron). Neurons are highly branched and polarized cells with neuronal processes extruding far from the nucleus and the cell body, in order to wire up and communicate with other neurons via specialized intercellular junctions (synapses). One neuron has thousands of synapses, so it is a big challenge for the neuron to tune thousands of synapses individually while orchestrating signal transduction and material transport through the whole cell.
Distribution of messenger RNAs at distal sites serves as a blueprint for the synthesis of specific proteins in response to the neuron-neuron communication. RNA localization at synapses enables fast and adaptive decision-making to direct local gene expression in complementary to centralized gene regulation in the nucleus. However, it is still unclear how RNAs are triaged, transported, stored, translated, and degraded with extraordinary precision in space and time.
Based on previous genetic and behavioral studies, chemical modification of RNAs is an indispensable element for proper synaptic functions, such as neurodevelopment and memory formation. However, there still lack tools to investigate further how RNA modifications achieve gene regulation at subcellular resolution. Dr. Wang is interested in developing new in situ sequencing methods to visualize RNA and their modification status at genome-wide inside neuronal cells. She will further apply this new tool to illustrate how RNA-based local gene regulation at synapses contributes to brain function.