@article{996ba3c3c34d422d8681aa3a15454c2f,
title = "Spatiotemporal and genetic regulation of A-to-I editing throughout human brain development",
abstract = "Posttranscriptional RNA modifications by adenosine-to-inosine (A-to-I) editing are abundant in the brain, yet elucidating functional sites remains challenging. To bridge this gap, we investigate spatiotemporal and genetically regulated A-to-I editing sites across prenatal and postnatal stages of human brain development. More than 10,000 spatiotemporally regulated A-to-I sites were identified that occur predominately in 3′ UTRs and introns, as well as 37 sites that recode amino acids in protein coding regions with precise changes in editing levels across development. Hyper-edited transcripts are also enriched in the aging brain and stabilize RNA secondary structures. These features are conserved in murine and non-human primate models of neurodevelopment. Finally, thousands of cis-editing quantitative trait loci (edQTLs) were identified with unique regulatory effects during prenatal and postnatal development. Collectively, this work offers a resolved atlas linking spatiotemporal variation in editing levels to genetic regulatory effects throughout distinct stages of brain maturation.",
keywords = "CP: Molecular biology, CP: Neuroscience, RNA modifications, RNA recoding, brain maturation, edQTLs, hyper-editing, late-fetal transition",
author = "Cuddleston, {Winston H.} and Xuanjia Fan and Laura Sloofman and Lindsay Liang and Enrico Mossotto and Kendall Moore and Sarah Zipkowitz and Minghui Wang and Bin Zhang and Jiebiao Wang and Nenad Sestan and Bernie Devlin and Kathryn Roeder and Sanders, {Stephan J.} and Buxbaum, {Joseph D.} and Breen, {Michael S.}",
note = "Funding Information: We thank the scientific community and the cited authors in this current study for making data publicly available for re-analysis. We acknowledge the A-to-I editing community and colleagues. We would like to thank the Seaver Autism Center for Research and Treatment for generous discussions and funding. M.S.B. is a Seaver Foundation Faculty Scholar. This work was supported by grant U01MH122678 from NIMH–Yale University School of Medicine (to N.S. and S.J.S.) and grants U01AG046170 (to B.Z.), U01AG052411 (to B.Z.), and RF1AG057440 (to B.Z.) from the NIA–Icahn School of Medicine at Mount Sinai. as well as grants R01MH129724 and R01MH111679 (to J.D.B.) from the NIMH–Icahn School of Medicine at Mount Sinai. Conceptualization, M.S.B. B.D. J.D.B. K.R. S.J.S. and N.D.; formal analysis, M.S.B. W.H.C. X.F. L.S. L.L. E.M. K.M. S.Z. M.W. and J.W.; validation and visualization, M.S.B. W.H.C. X.F. K.M. and S.Z.; writing – original draft, M.S.B. W.H.C. X.F. L.S. L.L. E.M. K.M. S.Z. M.W. J.W. J.D.B. S.J.S. K.R. and B.D.; writing – review & editing, M.S.B. B.D. and K.R.; funding acquisition, M.S.B. J.D.B. S.J.S. K.R. N.S. B.Z. and B.D.; supervision, M.S.B. J.D.B. S.J.S. K.R. and B.D. M.S.B. is a consultant for Shape Therapeutics. J.D.B. is a consultant for BridgeBio Pharma. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as a gender minority in their field of research. One or more of the authors of this paper received support from a program designed to increase minority representation in their field of research. Funding Information: We thank the scientific community and the cited authors in this current study for making data publicly available for re-analysis. We acknowledge the A-to-I editing community and colleagues. We would like to thank the Seaver Autism Center for Research and Treatment for generous discussions and funding. M.S.B. is a Seaver Foundation Faculty Scholar. This work was supported by grant U01MH122678 from NIMH–Yale University School of Medicine (to N.S. and S.J.S.) and grants U01AG046170 (to B.Z.), U01AG052411 (to B.Z.), and RF1AG057440 (to B.Z.) from the NIA–Icahn School of Medicine at Mount Sinai., as well as grants R01MH129724 and R01MH111679 (to J.D.B.) from the NIMH–Icahn School of Medicine at Mount Sinai. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = nov,
day = "1",
doi = "10.1016/j.celrep.2022.111585",
language = "English",
volume = "41",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}