Unbiased Identification of trans Regulators of ADAR and A-to-I RNA Editing

Freund, Emily C.; Sapiro, Anne L.; Li, Qin; Linder, Sandra; Moresco, James J.; Yates, John R.

doi:10.1016/j.celrep.2020.107656

Cited by 49 publications

(39 citation statements)

References 63 publications

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“…An additional layer of complexity may also arise from poorly understood ‘adaptive mechanisms’ which increase the density of the fully edited (VGV) HTR2C receptor at the cell membranes, very likely compensating for its diminished activity ( Kawahara et al, 2008 ; Morabito et al, 2010a ; Olaghere da Silva et al, 2010 ). Finally, how site-specific RNA editing is regulated remains a topic of intense research ( Freund et al, 2020 and references therein). Initial studies based on Sanger sequencing methods claimed that Htr2c editing is dynamically regulated in a context-dependent manner, particularly depending on serotonin levels ( Schmauss, 2003 ).…”

Section: Discussionmentioning

confidence: 99%

Reassessment of the involvement of Snord115 in the serotonin 2c receptor pathway in a genetically relevant mouse model

Hebras

Marty

Personnaz

et al. 2020

eLife

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SNORD115 has been proposed to promote the activity of serotonin (HTR2C) receptor via its ability to base-pair with its pre-mRNA and regulate alternative RNA splicing and/or A-to-I RNA editing. Because SNORD115 genes are deleted in most patients with the Prader-Willi syndrome (PWS), diminished HTR2C receptor activity could contribute to the impaired emotional response and/or compulsive overeating characteristic of this disease. In order to test this appealing but never demonstrated hypothesis in vivo, we created a CRISPR/Cas9-mediated Snord115 knockout mouse. Surprisingly, we uncovered only modest region-specific alterations in Htr2c RNA editing profiles while Htr2c alternative RNA splicing was unchanged. These subtle changes, whose functional relevance remains uncertain, were not accompanied by any discernible defects in anxio-depressive-like phenotypes. Energy balance and eating behaviour were also normal, even after exposure to high fat diet. Our study raises questions concerning the physiological role of SNORD115, notably its involvement in behavioural disturbance associated with PWS.

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Section: Discussionmentioning

confidence: 99%

Reassessment of the involvement of Snord115 in the serotonin 2c receptor pathway in a genetically relevant mouse model

Hebras

Marty

Personnaz

et al. 2020

eLife

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“…Biological evidence for such a complex is lacking. Recent mass spectrometry approaches to identify ADAR associated proteins that regulate inosine RNA modifications have not identified CCR4-NOT complex components [ 41 ]. Rather, several components of the ribosome were identified directly associated with ADAR [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Loss of Cnot6l Impairs Inosine RNA Modifications in Mouse Oocytes

Brachova

Alvarez

Christenson

2021

IJMS

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Mammalian oocytes must degrade maternal transcripts through a process called translational mRNA decay, in which maternal mRNA undergoes translational activation, followed by deadenylation and mRNA decay. Once a transcript is translationally activated, it becomes deadenylated by the CCR4-NOT complex. Knockout of CCR4-NOT Transcription Complex Subunit 6 Like (Cnot6l), a deadenylase within the CCR4-NOT complex, results in mRNA decay defects during metaphase I (MI) entry. Knockout of B-cell translocation gene-4 (Btg4), an adaptor protein of the CCR4-NOT complex, results in mRNA decay defects following fertilization. Therefore, mechanisms controlling mRNA turnover have significant impacts on oocyte competence and early embryonic development. Post-transcriptional inosine RNA modifications can impact mRNA stability, possibly through a translation mechanism. Here, we assessed inosine RNA modifications in oocytes, eggs, and embryos from Cnot6l-/- and Btg4-/- mice, which display stabilization of mRNA and over-translation of the stabilized transcripts. If inosine modifications have a role in modulating RNA stability, we hypothesize that in these mutant backgrounds, we would observe changes or a disruption in inosine mRNA modifications. To test this, we used a computational approach to identify inosine RNA modifications in total and polysomal RNA-seq data during meiotic maturation (GV, MI, and MII stages). We observed pronounced depletion of inosine mRNA modifications in samples from Cnot6l-/-, but not in Btg4-/- mice. Additionally, analysis of ribosome-associated RNA revealed clearance of inosine modified mRNA. These observations suggest a novel mechanism of mRNA clearance during oocyte maturation, in which inosine-containing transcripts decay in an independent, but parallel mechanism to CCR4-NOT deadenylation.

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“…Biological evidence for such a complex is lacking. Recent mass spectrometry approaches to identify ADAR associated proteins that regulate inosine RNA modifications have not identified CCR4-NOT complex components (Freund et al 2020). Rather, several components of the ribosome were identified directly associated with ADAR (Freund et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Loss ofCnot6limpairs inosine RNA modifications in mouse oocytes

Brachova

Alvarez

Christenson

2020

Preprint

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Mammalian oocytes must degrade maternal transcripts through a process called translational mRNA decay, in which maternal mRNA undergoes translational activation, followed by deadenylation and mRNA decay. Once a transcript is translationally activated, it becomes deadenylated by the CCR4-NOT complex. Knockout of Cnot6l, a deadenylase within the CCR4-NOT complex, results in mRNA decay defects during MI entry. Knockout of Btg4, an adaptor protein of the CCR4-NOT complex, results in mRNA decay defects following fertilization. Therefore, mechanisms controlling mRNA turnover have significant impacts on oocyte competence and early embryonic development. Post-transcriptional inosine RNA modifications can impact mRNA stability, possibly through a translation mechanism. Here, we assessed inosine RNA modifications in oocytes from Cnot6l-/- and Btg4-/-mice, which display stabilization of mRNA and over-translation of the stabilized transcripts. If inosine modifications have a role in modulating RNA stability, we hypothesize that in these mutant backgrounds, we would observe changes or a disruption in inosine mRNA modifications. To test this, we used a computational approach to identify inosine RNA modifications in total and ribosome-associated mRNA-seq data during meiotic maturation (GV, MI, and MII stages). We observed pronounced depletion of inosine mRNA modifications in oocytes from Cnot6l-/-, but not in Btg4-/- mice. Additionally, analysis of ribosome-associated RNA revealed clearance of inosine modified mRNA. These observations suggest a novel mechanism of mRNA clearance during oocyte maturation, in which inosine-containing transcripts decay in an independent, but parallel mechanism to CCR4-NOT deadenylation.

show abstract

Unbiased Identification of trans Regulators of ADAR and A-to-I RNA Editing

Cited by 49 publications

References 63 publications

Reassessment of the involvement of Snord115 in the serotonin 2c receptor pathway in a genetically relevant mouse model

Reassessment of the involvement of Snord115 in the serotonin 2c receptor pathway in a genetically relevant mouse model

Loss of Cnot6l Impairs Inosine RNA Modifications in Mouse Oocytes

Loss ofCnot6limpairs inosine RNA modifications in mouse oocytes

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