Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein

Bhogal, Balpreet; Jepson, James E.C.; Savva, Yiannis A.; Pepper, Anita S.-R.; Reenan, Robert A.; Jongens, Thomas A.

doi:10.1038/nn.2950

Cited by 80 publications

(77 citation statements)

References 50 publications

(74 reference statements)

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“…Our findings do not preclude the possibility that editing in other tissues may be affected by ADAR polymorphisms or by other proteins. In mammals, most A-to-I editing occurs in the brain, and in Drosophila, the fragile X mental retardation protein (FMRP) has been shown to affect editing at distant sites (Bhogal et al 2011). In future studies it will be important to use natural genetic variation in the mouse to assess long-and short-range influences on RNA editing in the brain.…”

Section: Discussionmentioning

confidence: 99%

Genetic Architectures of Quantitative Variation in RNA Editing Pathways

Gatti

Srivastava

et al. 2015

Genetics

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RNA editing refers to post-transcriptional processes that alter the base sequence of RNA. Recently, hundreds of new RNA editing targets have been reported. However, the mechanisms that determine the specificity and degree of editing are not well understood. We examined quantitative variation of site-specific editing in a genetically diverse multiparent population, Diversity Outbred mice, and mapped polymorphic loci that alter editing ratios globally for C-to-U editing and at specific sites for A-to-I editing. An allelic series in the C-to-U editing enzyme Apobec1 influences the editing efficiency of Apob and 58 additional C-to-U editing targets. We identified 49 A-to-I editing sites with polymorphisms in the edited transcript that alter editing efficiency. In contrast to the shared genetic control of C-to-U editing, most of the variable A-to-I editing sites were determined by local nucleotide polymorphisms in proximity to the editing site in the RNA secondary structure. Our results indicate that RNA editing is a quantitative trait subject to genetic variation and that evolutionary constraints have given rise to distinct genetic architectures in the two canonical types of RNA editing.KEYWORDS genetics; RNA editing; Diversity Outbred; Apobec1; secondary structure; Multiparent Advanced Generation Inter-Cross (MAGIC); multiparental populations; MPP R NA EDITING in mammals occurs through deamination of adenosine, which is converted to inosine (A-to-I editing), or deamination of cytosine, which is converted to uracil (C-to-U editing) (Davidson and Shelness 2000;Bass 2002). Other types of editing have been reported, but these findings remain controversial (Bass et al. 2012;Gu et al. 2012). The two canonical editing types, A-to-I and C-to-U editing, are mediated by distinct pathways. A-to-I editing is catalyzed on double-stranded (ds) RNA by proteins in the adenosine deaminase, RNA-specific (ADAR) family (ADAR1 and ADAR2) and is most common in neuronal tissues. However, the Adar gene family is ubiquitously expressed, and editing has been reported in many other tissues (Gu et al. 2012).Homozygous deletion of Adar genes is embryonic lethal in mice, and defects in A-to-I editing have been associated with neurodegenerative disorders and cancers (Gurevich et al. 2002;Paz et al. 2007). The C-to-U editing pathway is catalyzed by apolipoprotein B messenger RNA (mRNA) editing enzyme catalytic polypeptide 1 (Apobec1), which is expressed primarily in small intestine and liver, where it targets the transcript of apolipoprotein B (Apob), converting a CAA (glutamine) codon within the coding sequence to a stop codon (UAA). This editing event results in two APOB protein isoforms, APOB48 from the edited transcript and APOB100 from the unedited transcript. Editing of Apob is evolutionarily conserved and occurs in mice, humans, and other mammals. The edited isoform APOB48 functions in the synthesis, assembly, and secretion of chylomicrons in the small intestine; the unedited isoform APOB100 is expressed in the liver and gives ris...

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Section: Discussionmentioning

confidence: 99%

Genetic Architectures of Quantitative Variation in RNA Editing Pathways

Gatti

Srivastava

et al. 2015

Genetics

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“…FMRP contains nuclear localization and export sequences that facilitate nucleocytoplasmic shuttling [55]. FMRP binds mRNA in the nucleus [56], and has been shown to regulate RNA editing [57,58]. Two FMRP isoforms (ISO6, ISO12) contain a unique C-terminus, which is absent in common isoforms, for example ISO1, ISO7, and contains a sequence that localizes FMRP to nuclear Cajal bodies [59].…”

Section: Molecular Functions Of Fmrp: Targets and Molecular Mechanismmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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“…Additional examples are summarized in Supplement 1, Supplemental Table S19 and Supplemental Figures S11-S15, where we show that RNA processing genes including MBNL1, PSPC1, FMR1, SFRS4, POLL, CELF1, SF1, ZNF638, RBM3, and HNRNPD, all change their splicing pattern in the analyzed RNA-seq experiments of ADAR-deficient cells. It is interesting to note that dFMR1, the Drosophila homolog of FMR1, was shown to modulate dADAR activity (Bhogal et al 2011).…”

Section: Splicing Regulation By Adarmentioning

confidence: 99%

Global regulation of alternative splicing by adenosine deaminase acting on RNA (ADAR)

Solomon

Oren

Safran

et al. 2013

RNA

111

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Alternative mRNA splicing is a major mechanism for gene regulation and transcriptome diversity. Despite the extent of the phenomenon, the regulation and specificity of the splicing machinery are only partially understood. Adenosine-to-inosine (A-to-I) RNA editing of pre-mRNA by ADAR enzymes has been linked to splicing regulation in several cases. Here we used bioinformatics approaches, RNA-seq and exon-specific microarray of ADAR knockdown cells to globally examine how ADAR and its A-to-I RNA editing activity influence alternative mRNA splicing. Although A-to-I RNA editing only rarely targets canonical splicing acceptor, donor, and branch sites, it was found to affect splicing regulatory elements (SREs) within exons. Cassette exons were found to be significantly enriched with A-to-I RNA editing sites compared with constitutive exons. RNAseq and exon-specific microarray revealed that ADAR knockdown in hepatocarcinoma and myelogenous leukemia cell lines leads to global changes in gene expression, with hundreds of genes changing their splicing patterns in both cell lines. This global change in splicing pattern cannot be explained by putative editing sites alone. Genes showing significant changes in their splicing pattern are frequently involved in RNA processing and splicing activity. Analysis of recently published RNA-seq data from glioblastoma cell lines showed similar results. Our global analysis reveals that ADAR plays a major role in splicing regulation. Although direct editing of the splicing motifs does occur, we suggest it is not likely to be the primary mechanism for ADAR-mediated regulation of alternative splicing. Rather, this regulation is achieved by modulating trans-acting factors involved in the splicing machinery.

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Modulation of dADAR-dependent RNA editing by the Drosophila fragile X mental retardation protein

Cited by 80 publications

References 50 publications

Genetic Architectures of Quantitative Variation in RNA Editing Pathways

Genetic Architectures of Quantitative Variation in RNA Editing Pathways

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Global regulation of alternative splicing by adenosine deaminase acting on RNA (ADAR)

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