Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

Czermak, Philipp; Amman, Fabian; Jantsch, Michael F.; Cimatti, Laura

doi:10.1080/15476286.2018.1480252

Cited by 15 publications

(16 citation statements)

References 39 publications

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“…High RNA editing of FLNB has been observed in the cardiovascular system (62% in the heart and 66% in the aorta) and musculoskeletal system. [44]. However, in ADAR2 -/- mouse hearts compared to wild-type mouse hearts FLNB editing was reduced by 24% (Fig 4).…”

Section: Resultsmentioning

confidence: 96%

“…Impaired FLNA editing has been linked to arterial remodeling, thickening of the left ventricular wall, and increased phosphorylation of the myosin light chain[22]. FLNB showed high expression in vascular tissues [44]. High RNA editing of FLNB has been observed in the cardiovascular system (62% in the heart and 66% in the aorta) and musculoskeletal system.…”

Section: Resultsmentioning

confidence: 99%

“…We propose that the elevated expression of FLNB and the decline of editing in ADAR2 -/- mouse heart tissues might be associated with the cardiovascular disease similar to FLNA. Since the editing of FLNB was correlated with FLNB expression in the mouse cerebral cortex [44] therefore, the mRNA level of FLNB in ADAR2 -/- hearts was also determined. No significant difference was observed in FLNB mRNA levels between ADAR2 -/- mouse heart tissues and wild-type mouse heart tissues (Fig 4).…”

Section: Resultsmentioning

confidence: 99%

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Modulation of ADAR mRNA expression in patients with congenital heart defects

et al. 2019

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Adenosine (A) to inosine (I) RNA editing is a hydrolytic deamination reaction catalyzed by the adenosine deaminase (ADAR) enzyme acting on double-stranded RNA. This posttranscriptional process diversifies a plethora of transcripts, including coding and noncoding RNAs. Interestingly, few studies have been carried out to determine the role of RNA editing in vascular disease. The aim of this study was to determine the potential role of ADARs in congenital heart disease. Strong downregulation of ADAR2 and increase in ADAR1 expression was observed in blood samples from congenital heart disease (CHD) patients. The decrease in expression of ADAR2 was in line with its downregulation in ventricular tissues of dilated cardiomyopathy patients. To further decipher the plausible regulatory pathway of ADAR2 with respect to heart physiology, miRNA profiling of ADAR2 was performed on tissues from ADAR2-/- mouse hearts. Downregulation of miRNAs (miR-29b, miR-405, and miR-19) associated with cardiomyopathy and cardiac fibrosis was observed. Moreover, the upregulation of miR-29b targets COL1A2 and IGF1, indicated that ADAR2 might be involved in cardiac myopathy. The ADAR2 target vascular development associated protein-coding gene filamin B (FLNB) was selected. The editing levels of FLNB were dramatically reduced in ADAR2 -/- mice; however, no observable changes in FLNB expression were noted in ADAR2 -/- mice compared to wild-type mice. This study proposes that sufficient ADAR2 enzyme activity might play a vital role in preventing cardiovascular defects.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Modulation of ADAR mRNA expression in patients with congenital heart defects

et al. 2019

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“…While editing of the Flna transcript is highest in the cardiovascular system and the large intestine, editing of Flnb is low (Stulićand Jantsch 2013). Instead, Flnb editing levels are highest in the cartilaginous tissue and muscle (Czermak et al 2018). Therefore, substrate-specific regulation must occur in these cases.…”

Section: Discussionmentioning

confidence: 99%

A high resolution A-to-I editing map in the mouse identifies editing events controlled by pre-mRNA splicing

et al. 2019

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Pre-mRNA-splicing and adenosine to inosine (A-to-I) RNA-editing occur mostly cotranscriptionally. During A-to-I editing, a genomically encoded adenosine is deaminated to inosine by adenosine deaminases acting on RNA (ADARs). Editing-competent stems are frequently formed between exons and introns. Consistently, studies using reporter assays have shown that splicing efficiency can affect editing levels. Here, we use Nascent-seq and identify ∼90,000 novel A-to-I editing events in the mouse brain transcriptome. Most novel sites are located in intronic regions. Unlike previously assumed, we show that both ADAR (ADAR1) and ADARB1 (ADAR2) can edit repeat elements and regular transcripts to the same extent. We find that inhibition of splicing primarily increases editing levels at hundreds of sites, suggesting that reduced splicing efficiency extends the exposure of intronic and exonic sequences to ADAR enzymes. Lack of splicing factors NOVA1 or NOVA2 changes global editing levels, demonstrating that alternative splicing factors can modulate RNA editing. Finally, we show that intron retention rates correlate with editing levels across different brain tissues. We therefore demonstrate that splicing efficiency is a major factor controlling tissue-specific differences in editing levels.

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“…S10). Editing at the Gria2 R/G-site or Flna and Flnb sites is located close to the 5 ′ splice site at position −2 (Higuchi et al 1993;Czermak et al 2018).…”

Section: The Impact Of Adar On Splicing Is Tissue-specificmentioning

confidence: 99%

ADAR-deficiency perturbs the global splicing landscape in mouse tissues

et al. 2020

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Adenosine-to-inosine RNA editing and pre-mRNA splicing largely occur cotranscriptionally and influence each other. Here, we use mice deficient in either one of the two editing enzymes ADAR (ADAR1) or ADARB1 (ADAR2) to determine the transcriptome-wide impact of RNA editing on splicing across different tissues. We find that ADAR has a 100× higher impact on splicing than ADARB1, although both enzymes target a similar number of substrates with a large common overlap. Consistently, differentially spliced regions frequently harbor ADAR editing sites. Moreover, catalytically dead ADAR also impacts splicing, demonstrating that RNA binding of ADAR affects splicing. In contrast, ADARB1 editing sites are found enriched 5 ′ of differentially spliced regions. Several of these ADARB1-mediated editing events change splice consensus sequences, therefore strongly influencing splicing of some mRNAs. A significant overlap between differentially edited and differentially spliced sites suggests evolutionary selection toward splicing being regulated by editing in a tissue-specific manner.

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Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

Cited by 15 publications

References 39 publications

Modulation of ADAR mRNA expression in patients with congenital heart defects

Modulation of ADAR mRNA expression in patients with congenital heart defects

A high resolution A-to-I editing map in the mouse identifies editing events controlled by pre-mRNA splicing

ADAR-deficiency perturbs the global splicing landscape in mouse tissues

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