Developmental Dynamics of RNA Translation in the Human Brain

The precise regulation of gene expression is fundamental to neurodevelopment, plasticity, and cognitive function. While several studies have profiled transcription in the developing human brain, there is a gap in our understanding of accompanying translational regulation. We performed ribosome profiling on 73 human prenatal and adult cortex samples. We characterized the translational regulation of annotated open reading frames (ORFs) and identified thousands of previously unknown translation events, including small ORFs that give rise to human- and/or brain-specific microproteins, many of which we independently verified using proteomics. Ribosome profiling in stem cell-derived human neuronal cultures corroborated these findings and revealed that several neuronal activity-induced non-coding RNAs encode previously undescribed microproteins. Physicochemical analysis of brain microproteins identified a class of proteins that contain arginine-glycine-glycine (RGG) repeats and thus may be regulators of RNA metabolism. This resource expands the known translational landscape of the human brain and illuminates previously unknown brain-specific protein products.