Chemistry and Biology Connected for the Emergence of Individual Cognition

Background and Aim: A brain is an intricate, complex, and beautifulorgan that underlies our cognition and behavior. Although we areliving in an era of privilege that we can not only read our own geneticmakeups, we are also becoming capable of editing them at will, weremain woefully ignorant of what all this means for the brain to becomecapable of constructing individual cognition.Methods: To solve this mystery, our group focus on the post-transcriptionalregulation mechanisms of RNA molecules and take three approaches tounderstand these cellular processes: to see, to analyze, and to mimic. Tosee the RNA molecules in living cells, we develop functional chemicalprobes for fluorescent labeling of the RNA. To analyze RNA in a genomewidemanner, we apply deep sequencing techniques and bioinformaticsanalysis. To mimic RNA regulation, we build artificial magneticnanoparticles to mimic naturally occurring cellular RNA granules. In thistalk, I will highlight our recent study how experience-driven activitiesin the brain is integrated into protein synthesis, at the close proximityto synapses of neurons. These proteins form multicomponent complexesand make up the microscopic machinery for neuronal plasticity andbehavior.Results: Recently, our group established a low-input sequencing methodto study the minute amount of synaptic RNA and reported the initial draftof epitranscriptome at synapses. About 4469 methylation sites enrichedin 2,921 genes as the synaptic m6A epitranscriptome (SME) wereidentified in biochemically enriched neuronal synapses. SME was foundto be functionally enriched in the synthesis and modulation of tripartite synapses as well as some pathways implicated in neurodevelopmentaland neuropsychiatric diseases. Interrupting m6A-mediated regulation viaknockdown of readers in hippocampal neurons was found to changethe expression of SME member Apc, resulting in synaptic dysfunctionsuch as immature spine morphology and dampened excitatory synaptictransmission concomitant with decreased PSD-95 clustering and GluA1surface expression.Conclusion: Our findings indicate that extremely simple chemicalmodifications, such as the addition of a methyl group (-CH3) to theRNA molecules, can make critical contributions to building neuronalcircuits in the brain and thus the emergence of individual cognitiveabilities. This study warrants further investigations on the diversechemical modifications at the synaptic RNA and their contribution toindividual cognition. Currently 171 RNA modifications are known innature, indicating our genetic programs can be expanded by orders ofmagnitude, which might be essential for creating diversity and complexityof neuronal connections.

کلیدواژه ها:

Synapse ، RNA modification ، Epitranscriptomics ، Neuronal circuitry ، Genetic information