@article{57bd2d9456594673b50d9ba8b12a7515,
title = "Developmental dynamics of RNA translation in the human brain",
abstract = "The precise regulation of gene expression is fundamental to neurodevelopment, plasticity and cognitive function. Although several studies have profiled transcription in the developing human brain, there is a gap in understanding of accompanying translational regulation. In this study, 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-specific 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.",
author = "Duffy, {Erin E.} and Benjamin Finander and Choi, {Gi Hun} and Carter, {Ava C.} and Iva Pritisanac and Aqsa Alam and Victor Luria and Amir Karger and William Phu and Sherman, {Maxwell A.} and Assad, {Elena G.} and Naomi Pajarillo and Alexandra Khitun and Crouch, {Elizabeth E.} and Sanika Ganesh and Jin Chen and Bonnie Berger and Nenad Sestan and Anne O{\textquoteright}Donnell-Luria and Huang, {Eric J.} and Griffith, {Eric C.} and Forman-Kay, {Julie D.} and Moses, {Alan M.} and Kalish, {Brian T.} and Greenberg, {Michael E.}",
note = "Funding Information: This research was supported by the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation. E.E.D. was supported by the Damon Runyon Cancer Research Foundation (DRG-2397-20). A.C.C. was supported by the Hanna H. Gray Fellowship through the Howard Hughes Medical Institute. V.L. was supported by a Boston Children{\textquoteright}s Hospital Career Development Award (to A.O.D.L.), and V.L. and N.S. were supported by National Human Genomic Research Institute (NHGRI) R01HG010898 and NIH 1R01HG010898-01A1. E.J.H. was supported by NIH P01 NS083513. A.O.D.L. and W.P. were supported by a Manton Center Endowed Scholar Award and NHGRI U01HG008900. M.A.S. was supported by National Institute of Mental Health (NIMH) F31MH124393. A.M.M. and J.D.F.-K. acknowledge funding from the Canadian Institutes of Health Research (CIHR PJT-148532). B.T.K. was supported by National Institute of Neurological Diseases and Stroke (NINDS) K08 NS112338. M.E.G. was supported by funding from NINDS R01 NS115965. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank members of the Greenberg laboratory for helpful discussions on the manuscript. We thank the Taplin Mass Spectrometry Facility at Harvard Medical School for their technical expertise and analysis of proteomics samples and S. Slavoff for advice on size-selection proteomics. We thank the Broad Institute Genomics Program for next-generation sequencing of ribosome profiling libraries. We are grateful to the NIH NeuroBioBank and the Human Developmental Biology Resource for providing human adult and prenatal brain tissue, respectively. We are grateful to the laboratory of D. Trono for sharing the human transposable element annotation and to W. Harper for reagents and technical advice related to iPSC-derived human neurons. We thank the Neurobiology Department and the Neurobiology Imaging Facility for consultation and instrument availability that supported this work. This facility is supported, in part, by the Neural Imaging Center as part of an NINDS P30 Core Center grant (NS072030). Figures , and were made with BioRender. Funding Information: This research was supported by the Allen Discovery Center program, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation. E.E.D. was supported by the Damon Runyon Cancer Research Foundation (DRG-2397-20). A.C.C. was supported by the Hanna H. Gray Fellowship through the Howard Hughes Medical Institute. V.L. was supported by a Boston Children{\textquoteright}s Hospital Career Development Award (to A.O.D.L.), and V.L. and N.S. were supported by National Human Genomic Research Institute (NHGRI) R01HG010898 and NIH 1R01HG010898-01A1. E.J.H. was supported by NIH P01 NS083513. A.O.D.L. and W.P. were supported by a Manton Center Endowed Scholar Award and NHGRI U01HG008900. M.A.S. was supported by National Institute of Mental Health (NIMH) F31MH124393. A.M.M. and J.D.F.-K. acknowledge funding from the Canadian Institutes of Health Research (CIHR PJT-148532). B.T.K. was supported by National Institute of Neurological Diseases and Stroke (NINDS) K08 NS112338. M.E.G. was supported by funding from NINDS R01 NS115965. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank members of the Greenberg laboratory for helpful discussions on the manuscript. We thank the Taplin Mass Spectrometry Facility at Harvard Medical School for their technical expertise and analysis of proteomics samples and S. Slavoff for advice on size-selection proteomics. We thank the Broad Institute Genomics Program for next-generation sequencing of ribosome profiling libraries. We are grateful to the NIH NeuroBioBank and the Human Developmental Biology Resource for providing human adult and prenatal brain tissue, respectively. We are grateful to the laboratory of D. Trono for sharing the human transposable element annotation and to W. Harper for reagents and technical advice related to iPSC-derived human neurons. We thank the Neurobiology Department and the Neurobiology Imaging Facility for consultation and instrument availability that supported this work. This facility is supported, in part, by the Neural Imaging Center as part of an NINDS P30 Core Center grant (NS072030). Figures 3d , 4a and 7d were made with BioRender. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = oct,
doi = "10.1038/s41593-022-01164-9",
language = "English (US)",
volume = "25",
pages = "1353--1365",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "10",
}