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

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

doi:10.1016/j.celrep.2022.111585

Cited by 13 publications

(22 citation statements)

References 105 publications

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“…The majority of RNA-editing was detected within intronic and 3’UTR gene regions, though some was found in the coding sequence (Figure 1D). We also detected that 88% and 87% of RNA-editing sites in progenitor and neurons were also previously identified in either GTEx Cortex 74 or BrainVar 55 data in which whole-genome-sequencing data paired to RNA-seq were available (Figure 1E), showing consistency of data generated here with previously discovered RNA-editing events. We further evaluated a common local sequence motif for RNA-editing, which is 1bp upstream enrichment and 1bp downstream depletion of guanosine 75 among the RNA-edit sites we discovered.…”

Section: Resultssupporting

confidence: 84%

“…Previous studies have reported that RNA-editing increases from fetal to adult human brain 41,55 . However, the mechanism causing the developmental increase of RNA-editing has remained unexplored.…”

Section: Discussionmentioning

confidence: 96%

“…As a potential mechanism for edQTLs, genetic variants can perturb RNA secondary structure, which can lead to differential RNA-editing in nearby regions 22,35,40 . Though adult brain bulk tissues are most commonly used to study edQTLs 35,46,54 , recent studies have shown that RNA-editing increases from development to adulthood in the human brain 41,55 , and edQTLs that were not observed in adult brain bulk tissue were detected in bulk fetal brain tissue 55 . Despite the discovery of temporal-specific edQTLs, the cell-type specificity of RNA-editing events and their genetic regulation are as yet unknown during human cortical development and may have been masked in previous bulk tissue studies due to heterogeneity in cell-type composition.…”

Section: Introductionmentioning

confidence: 99%

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Genetics of cell-type-specific post-transcriptional gene regulation during human neurogenesis

Aygün,

Krupa,

Mory

et al. 2023

Preprint

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The function of some genetic variants associated with brain-relevant traits has been explained through colocalization with expression quantitative trait loci (eQTL) conducted in bulk post-mortem adult brain tissue. However, many brain-trait associated loci have unknown cellular or molecular function. These genetic variants may exert context-specific function on different molecular phenotypes including post-transcriptional changes. Here, we identified genetic regulation of RNA-editing and alternative polyadenylation (APA), within a cell-type-specific population of human neural progenitors and neurons. More RNA-editing and isoforms utilizing longer polyadenylation sequences were observed in neurons, likely due to higher expression of genes encoding the proteins mediating these post-transcriptional events. We also detected hundreds of cell-type-specific editing quantitative trait loci (edQTLs) and alternative polyadenylation QTLs (apaQTLs). We found colocalizations of a neuron edQTL in CCDC88A with educational attainment and a progenitor apaQTL in EP300 with schizophrenia, suggesting genetically mediated post-transcriptional regulation during brain development lead to differences in brain function.

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Section: Resultssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Genetics of cell-type-specific post-transcriptional gene regulation during human neurogenesis

Aygün,

Krupa,

Mory

et al. 2023

Preprint

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“…This is in line with previous research findings 32,33 . Given that A-to-I editing is the most prevalent type of editing and has significant impacts on development [34][35][36] , we chose to focus our subsequent analysis solely on this type of editing.…”

Section: Characterization Of High-confidence A-to-i Editing Sites Acr...mentioning

confidence: 99%

Temporal landscape and translational regulation of A-to-I editing in mouse retina development

Yang

Liang

Yang

et al. 2023

Preprint

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The significance of A-to-I RNA editing in neurological development is widely recognized, however, its influence on retina development remains to be thoroughly understood. In this study, we aimed to characterize the temporal landscape of A-to-I editing in mouse retina development using total RNA-seq and Ribosome profiling, with a specific emphasis on its effect on gene translation. Our findings revealed that the editing underwent plastic changes and distinct editing contents facilitated stage-specific functions. Further analysis showed a dynamic interplay between A-to-I editing and alternative splicing, with A-to-I editing having a significant impact on splicing efficiency and increasing the quantity of splicing events. A-to-I editing held the potential of enhancing the translatome's diversity, but this came at the expense of reduced translational efficiency. When coupled with splicing, it could produce a coordinated regulatory effect on translatome dynamics. Overall, our study presents a temporally resolved atlas of A-to-I editing, connecting its dynamic changes with the regulatory impact on splicing and translation.

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“…ADAR3 (ADARB2) is expressed exclusively in the brain but cannot catalyze A-to-I activity and is proposed to be a negative regulator of A-to-I editing 12,13 . In the mammalian brain, thousands of highly regulated A-to-I editing sites have been discovered across anatomical regions and cell types [13][14][15] as well as neuronal maturation and brain development [16][17][18] . Aberrant regulation of A-to-I editing in the brain has also been linked to the etiology of several neurological disorders [19][20][21][22][23] , further underscoring the physiological significance of A-to-I editing in the CNS.…”

Section: Introductionmentioning

confidence: 99%

Divergent landscapes of A-to-I editing in postmortem and living human brain

Rodriguez de los Santos,

Kopell,

Buxbaum Grice

et al. 2024

Preprint

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Adenosine-to-inosine (A-to-I) editing is a prevalent post-transcriptional RNA modification within the brain. Yet, most research has relied on postmortem samples, assuming it is an accurate representation of RNA biology in the living brain. We challenge this assumption by comparing A-to-I editing between postmortem and living prefrontal cortical tissues. Major differences were found, with over 70,000 A-to-I sites showing higher editing levels in postmortem tissues. Increased A-to-I editing in postmortem tissues is linked to higher ADAR1 and ADARB1 expression, is more pronounced in non-neuronal cells, and indicative of postmortem activation of inflammation and hypoxia. Higher A-to-I editing in living tissues marks sites that are evolutionarily preserved, synaptic, developmentally timed, and disrupted in neurological conditions. Common genetic variants were also found to differentially affect A-to-I editing levels in living versus postmortem tissues. Collectively, these discoveries illuminate the nuanced functions and intricate regulatory mechanisms of RNA editing within the human brain.

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

Cited by 13 publications

References 105 publications

Genetics of cell-type-specific post-transcriptional gene regulation during human neurogenesis

Genetics of cell-type-specific post-transcriptional gene regulation during human neurogenesis

Temporal landscape and translational regulation of A-to-I editing in mouse retina development

Divergent landscapes of A-to-I editing in postmortem and living human brain

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