A survey of RNA editing at single-cell resolution links interneurons to schizophrenia and autism.
A survey of RNA editing at single-cell resolution links interneurons to schizophrenia and autism.
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DOI：
10.1261/rna.078804.121
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Bahlo M
中科院分区：
文献类型：
--
作者：
Ansell BRE;Thomas SN;Bonelli R;Munro JE;Freytag S;Bahlo M
通过阿达尔酶将RNA中的腺苷转化为肌苷，称为“RNA编辑”，对健康的大脑发育至关重要。编辑在神经精神疾病中失调，但尚未在单个神经元水平上进行大规模研究。我们量化了来自神经典型女性供体的6个皮质区域的3055个神经元的核转录组中的RNA编辑位点，并在至少10个核中发现了41，930个位点。大多数位点位于内含子或3′ UTR中的Alu重复序列内，约80%的位点被收录在公共RNA编辑数据库中。我们确定了9285个推定的新编辑位点，其中29%在无关供体中也可检测到。与批量RNA-seq研究结果的交叉提供了精神分裂症脑供体中1730个差异编辑位点的细胞类型和空间背景，以及自闭症供体中910个此类位点。自闭症相关基因也富含预测修饰RNA结构的编辑位点。抑制性神经元比兴奋性神经元显示出更高的整体转录组编辑，并且在额叶皮层中观察到最高的编辑率。我们使用广义线性模型来识别细胞类型之间的差异编辑位点和基因。29个基因在兴奋性神经元中被优先编辑，43个基因在抑制性神经元中被更大量地编辑，包括RBFOX 1、其靶基因和自闭症相关的Prader-Willi基因座（15 q11）中的基因。来自基因座15 q11的SNORD 115/116基因的丰度与转录组的编辑活性正相关。我们认为，抑制性神经元中自闭症相关基因的编辑不足可能导致自闭症细胞的特定扰动。
Conversion of adenosine to inosine in RNA by ADAR enzymes, termed “RNA editing,” is essential for healthy brain development. Editing is dysregulated in neuropsychiatric diseases, but has not yet been investigated at scale at the level of individual neurons. We quantified RNA editing sites in nuclear transcriptomes of 3055 neurons from six cortical regions of a neurotypical female donor, and found 41,930 sites present in at least ten nuclei. Most sites were located within Alu repeats in introns or 3′ UTRs, and approximately 80% were cataloged in public RNA editing databases. We identified 9285 putative novel editing sites, 29% of which were also detectable in unrelated donors. Intersection with results from bulk RNA-seq studies provided cell-type and spatial context for 1730 sites that are differentially edited in schizophrenic brain donors, and 910 such sites in autistic donors. Autism-related genes were also enriched with editing sites predicted to modify RNA structure. Inhibitory neurons showed higher overall transcriptome editing than excitatory neurons, and the highest editing rates were observed in the frontal cortex. We used generalized linear models to identify differentially edited sites and genes between cell types. Twenty nine genes were preferentially edited in excitatory neurons, and 43 genes were edited more heavily in inhibitory neurons, including RBFOX1, its target genes, and genes in the autism-associated Prader–Willi locus (15q11). The abundance of SNORD115/116 genes from locus 15q11 was positively associated with editing activity across the transcriptome. We contend that insufficient editing of autism-related genes in inhibitory neurons may contribute to the specific perturbation of those cells in autism.
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DOI：
10.1073/pnas.1507125112
发表时间：
2015-06-09
影响因子：
11.1
作者：
Darmanis S;Sloan SA;Zhang Y;Enge M;Caneda C;Shuer LM;Hayden Gephart MG;Barres BA;Quake SR
通讯作者：
Quake SR
影响因子：
5.2
作者：
Bieth, Eric;Eddiry, Sanaa;Tauber, Maithe
通讯作者：
Tauber, Maithe
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
2
作者：
Descheemaeker, MJ;Govers, V;Fryns, JP
通讯作者：
Fryns, JP
影响因子：
--
作者：
Chen Y;Pal B;Visvader JE;Smyth GK
通讯作者：
Smyth GK