Spatiotemporal and genetic regulation of A-to-I editing throughout human brain development

Winston H. Cuddleston, Xuanjia Fan, Laura Sloofman, Lindsay Liang, Enrico Mossotto, Kendall Moore, Sarah Zipkowitz, Minghui Wang, Bin Zhang, Jiebiao Wang, Nenad Sestan, Bernie Devlin, Kathryn Roeder, Stephan J. Sanders, Joseph D. Buxbaum, Michael S. Breen

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number111585
JournalCell Reports
Volume41
Issue number5
DOIs
StatePublished - 1 Nov 2022

Keywords

  • CP: Molecular biology
  • CP: Neuroscience
  • RNA modifications
  • RNA recoding
  • brain maturation
  • edQTLs
  • hyper-editing
  • late-fetal transition

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