Dataset Information

Spatially regulated editing of genetic information within a neuron.

ABSTRACT: In eukaryotic cells, with the exception of the specialized genomes of mitochondria and plastids, all genetic information is sequestered within the nucleus. This arrangement imposes constraints on how the information can be tailored for different cellular regions, particularly in cells with complex morphologies like neurons. Although messenger RNAs (mRNAs), and the proteins that they encode, can be differentially sorted between cellular regions, the information itself does not change. RNA editing by adenosine deamination can alter the genome's blueprint by recoding mRNAs; however, this process too is thought to be restricted to the nucleus. In this work, we show that ADAR2 (adenosine deaminase that acts on RNA), an RNA editing enzyme, is expressed outside of the nucleus in squid neurons. Furthermore, purified axoplasm exhibits adenosine-to-inosine activity and can specifically edit adenosines in a known substrate. Finally, a transcriptome-wide analysis of RNA editing reveals that tens of thousands of editing sites (>70% of all sites) are edited more extensively in the squid giant axon than in its cell bodies. These results indicate that within a neuron RNA editing can recode genetic information in a region-specific manner.

SUBMITTER: Vallecillo-Viejo IC

PROVIDER: S-EPMC7192619 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Spatially regulated editing of genetic information within a neuron.

Vallecillo-Viejo Isabel C IC Liscovitch-Brauer Noa N Diaz Quiroz Juan F JF Montiel-Gonzalez Maria F MF Nemes Sonya E SE Rangan Kavita J KJ Levinson Simon R SR Eisenberg Eli E Rosenthal Joshua J C JJC

Nucleic acids research 20200501 8

In eukaryotic cells, with the exception of the specialized genomes of mitochondria and plastids, all genetic information is sequestered within the nucleus. This arrangement imposes constraints on how the information can be tailored for different cellular regions, particularly in cells with complex morphologies like neurons. Although messenger RNAs (mRNAs), and the proteins that they encode, can be differentially sorted between cellular regions, the information itself does not change. RNA editing ...[more]

PMID: 32201888

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Project description:Adenosine-to-inosine (A-to-I) RNA editing is a co-/posttranscriptional modification of double-stranded RNA, catalyzed by the adenosine deaminase acting on RNA (ADAR) family of enzymes, which results in recognition of inosine as guanosine by translational and splicing machinery causing potential recoding events in amino acid sequences. A-to-I editing is prominent within brain-specific transcripts, and dysregulation of editing at several well-studied loci (e.g., Gria2, Htr2c) has been implicated in acute and chronic stress in rodents as well as neurological (e.g., Alzheimer's) and psychopathological disorders such as schizophrenia and major depressive disorder. However, only a small fraction of recoding sites has been investigated within the brain following stress, and our understanding of the role of RNA editing in transcriptome regulation following environmental stimuli remains poorly understood. Thus, we aimed to investigate A-to-I editing at hundreds of loci following chronic social defeat stress (CSDS) in mice within corticolimbic regions responsive to chronic stress regulation. Adult male mice were subjected to CSDS or control conditions for 21 days and dynamic regulation of A-to-I editing was investigated 2 and 8 days following the final defeat within both the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). Employing a targeted resequencing approach, which utilizes microfluidics-based multiplex polymerase chain reaction (PCR) coupled with next-generation sequencing, we analyzed A-to-I editing at ∼100 high-confidence editing sites within the mouse brain. CSDS resulted in acute regulation of transcripts encoding several ADAR enzymes, which normalized 8 days following the final defeat and was specific for susceptible mice. In contrast, sequencing analysis revealed modest and dynamic regulation of A-to-I editing within numerous transcripts in both the mPFC and BLA of resilient and susceptible mice at both 2 and 8 days following CSDS with minimal overlap between regions and time points. Editing within the Htr2c transcript and relative abundance of Htr2c messenger RNA (mRNA)variants were also observed within the BLA of susceptible mice 2 days following CSDS. These results indicate dynamic RNA editing within discrete brain regions following CSDS in mice, further implicating A-to-I editing as a stress-sensitive molecular mechanism within the brain of potential relevance to resiliency and susceptibility to CSDS.

Dataset Information

Spatially regulated editing of genetic information within a neuron.

Publications

Spatially regulated editing of genetic information within a neuron.

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