A-to-I editing of microRNAs in the mammalian brain increases during development

Ekdahl, Ylva; Farahani, Hossein; Behm, Mikaela; Lagergren, Jens; Öhman, Marie

doi:10.1101/gr.131912.111

Cited by 102 publications

(109 citation statements)

References 47 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In wild-type worms, few small RNAs are produced over these regions while abundant small RNAs are observed in adr-1;adr-2 mutant animals, suggesting that ADAR competes with the RNAi machinery to engage these substrates, a recurring theme in multiple studies (Ekdahl et al 2012;Vesely et al 2012;Warf et al 2012). The authors determined that a subset of ARLs (184) was edited, suggesting there might be overlap between our data sets.…”

Section: Comparison Of Eer Data Sets With Data Sets Of Related Studiesmentioning

confidence: 99%

Genome-wide profiling of the C. elegans dsRNAome

Whipple

Youssef

Aruscavage

et al. 2015

RNA

View full text Add to dashboard Cite

Recent studies hint that endogenous dsRNA plays an unexpected role in cellular signaling. However, a complete understanding of endogenous dsRNA signaling is hindered by an incomplete annotation of dsRNA-producing genes. To identify dsRNAs expressed in Caenorhabditis elegans, we developed a bioinformatics pipeline that identifies dsRNA by detecting clustered RNA editing sites, which are strictly limited to long dsRNA substrates of Adenosine Deaminases that act on RNA (ADAR). We compared two alignment algorithms for mapping both unique and repetitive reads and detected as many as 664 editing-enriched regions (EERs) indicative of dsRNA loci. EERs are visually enriched on the distal arms of autosomes and are predicted to possess strong internal secondary structures as well as sequence complementarity with other EERs, indicative of both intramolecular and intermolecular duplexes. Most EERs were associated with protein-coding genes, with ∼1.7% of all C. elegans mRNAs containing an EER, located primarily in very long introns and in annotated, as well as unannotated, 3 ′ UTRs. In addition to numerous EERs associated with coding genes, we identified a population of prospective noncoding EERs that were distant from protein-coding genes and that had little or no coding potential. Finally, subsets of EERs are differentially expressed during development as well as during starvation and infection with bacterial or fungal pathogens. By combining RNA-seq with freely available bioinformatics tools, our workflow provides an easily accessible approach for the identification of dsRNAs, and more importantly, a catalog of the C. elegans dsRNAome.

show abstract

Section: Comparison Of Eer Data Sets With Data Sets Of Related Studiesmentioning

confidence: 99%

Genome-wide profiling of the C. elegans dsRNAome

Whipple

Youssef

Aruscavage

et al. 2015

RNA

View full text Add to dashboard Cite

show abstract

“…We have previously shown that A-to-I RNA editing increases in both coding and non-coding substrates in the developing mouse brain (Ekdahl et al, 2012;Wahlstedt et al, 2009). To study the mechanisms that regulate A-to-I editing during neuronal maturation, we isolated cortical neural progenitor cells from mouse cortices at embryonic day 16 and cultured them for up to 14 days in vitro (DIV).…”

Section: Rna Editing Increases In Cultured Primary Cortical Neurons Amentioning

confidence: 99%

“…S1A). To determine if editing increased in a similar way in developing cultured neurons as in the brain, coding as well as non-coding RNA substrates with both specific and overlapping specificity for ADAR1 and ADAR2 editing were selected for analyses after 1-12 days in culture (Ekdahl et al, 2012;Nishimoto et al, 2008;Ohlson et al, 2007). Similar to that in the embryonic brain, low levels of editing were observed at the I/M site in the coding region of the Gabra-3 transcript and at the +6 site in the miRNA precursor transcript pri-miR-376b after 1 DIV (Fig.…”

Section: Rna Editing Increases In Cultured Primary Cortical Neurons Amentioning

confidence: 99%

“…Although most A-to-I editing sites within these repetitive elements have not been assigned specific functions, there are examples where editing leads to alternative splicing and exonization of introns (Lev-Maor et al, 2007). The non-coding microRNAs (miRNAs) are also edited, particularly in the targeting seed sequence (Alon et al, 2012;Ekdahl et al, 2012;Kawahara et al, 2007;Vesely et al, 2014). The ADAR enzymes target the nuclear miRNA precursors and can affect their maturation or mRNA-targeting capacity.…”

Section: Introductionmentioning

confidence: 99%

“…The ADAR enzymes target the nuclear miRNA precursors and can affect their maturation or mRNA-targeting capacity. The frequency of miRNA editing is also a regulated event during brain development (Ekdahl et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Accumulation of nuclear ADAR2 regulates adenosine-to-inosine RNA editing during neuronal development

Behm

Wahlstedt

Widmark

et al. 2017

Journal of Cell Science

Self Cite

View full text Add to dashboard Cite

Adenosine to inosine (A-to-I) RNA editing is important for a functional brain, and most known sites that are subject to selective RNA editing have been found to result in diversified protein isoforms that are involved in neurotransmission. In the absence of the active editing enzymes ADAR1 or ADAR2 (also known as ADAR and ADARB1, respectively), mice fail to survive until adulthood. Nuclear A-to-I editing of neuronal transcripts is regulated during brain development, with low levels of editing in the embryo and a dramatic increase after birth. Yet, little is known about the mechanisms that regulate editing during development. Here, we demonstrate lower levels of ADAR2 in the nucleus of immature neurons than in mature neurons. We show that importin-α4 (encoded by Kpna3), which increases during neuronal maturation, interacts with ADAR2 and contributes to the editing efficiency by bringing it into the nucleus. Moreover, we detect an increased number of interactions between ADAR2 and the nuclear isomerase Pin1 as neurons mature, which contribute to ADAR2 protein stability. Together, these findings explain how the nuclear editing of substrates that are important for neuronal function can increase as the brain develops.

show abstract

ADAR1, inosine and the immune sensing system: distinguishing self from non‐self

2015

View full text Add to dashboard Cite

The conversion of genomically encoded adenosine to inosine in dsRNA is termed as A-to-I RNA editing. This process is catalyzed by two of the three mammalian ADAR proteins (ADAR1 and ADAR2) both of which have essential functions for normal organismal homeostasis. The phenotype of ADAR2 deficiency can be primarily ascribed to a lack of site-selective editing of a single transcript in the brain. In contrast, the biology and substrates responsible for the Adar1(-/-) phenotype have remained more elusive. Several recent studies have identified that a feature of absence or reductions of ADAR1 activity, conserved across human and mouse models, is a profound activation of interferon-stimulated gene signatures and innate immune responses. Further analysis of this observation has lead to the conclusion that editing by ADAR1 is required to prevent activation of the cytosolic innate immune system, primarily focused on the dsRNA sensor MDA5 and leading to downstream signaling via MAVS. The delineation of this mechanism places ADAR1 at the interface between the cells ability to differentiate self- from non-self dsRNA. Based on MDA5 dsRNA recognition requisites, the mechanism indicates that the type of dsRNA must fulfil a particular structural characteristic, rather than a sequence-specific requirement. While additional studies are required to molecularly verify the genetic model, the observations to date collectively identify A-to-I editing by ADAR1 as a key modifier of the cellular response to endogenous dsRNA.

show abstract

A-to-I editing of microRNAs in the mammalian brain increases during development

Cited by 102 publications

References 47 publications

Genome-wide profiling of the C. elegans dsRNAome

Genome-wide profiling of the C. elegans dsRNAome

Accumulation of nuclear ADAR2 regulates adenosine-to-inosine RNA editing during neuronal development

ADAR1, inosine and the immune sensing system: distinguishing self from non‐self

Contact Info

Product

Resources

About