Developmental Dynamics of RNA Translation in the Human Brain

Abstract

The precise regulation of gene expression is fundamental to neurodevelopment, plasticity, and cognitive function. While several studies have deeply profiled mRNA dynamics in the developing human brain, there is a fundamental gap in our understanding of accompanying translational regulation. We perform ribosome profiling from more than 70 human prenatal and adult cortex samples across ontogeny and into adulthood, mapping translation events at nucleotide resolution. In addition to characterizing the translational regulation of annotated open reading frames (ORFs), we identify thousands of previously unknown translation events, including small open reading frames (sORFs) that give rise to human- and/or brain-specific microproteins, many of which we independently verify using size-selected proteomics. Ribosome profiling in stem cell-derived human neuronal cultures further corroborates these findings and shows that several neuronal activity-induced long non-coding RNAs (lncRNAs), including LINC00473, a primate-specific lncRNA implicated in depression, encode previously undescribed microproteins. Physicochemical analysis of these brain microproteinss identifies a large class harboring arginine-glycine-glycine (RGG) repeats as strong candidates for regulating RNA metabolism. Moreover, we find that, collectively, these previously unknown human brain sORFs are enriched for variants associated with schizophrenia. In addition to significantly expanding the translational landscape of the developing brain, this atlas will serve as a rich resource for the annotation and functional interrogation of thousands of previously unknown brain-specific protein products.