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Identification of the long, edited dsRNAome in LPS-stimulated bone marrow-derived macrophages (BMDMs)

ABSTRACT: Endogenous double-stranded RNA (dsRNA) is intricately regulated in mammals to prevent aberrant activation of host inflammatory pathways by cytosolic dsRNA binding proteins. We define the endogenous dsRNA repertoire in mouse BMDMs during the inflammatory response to bacterial lipopolysaccharide. Editing by adenosine deaminases that act of RNA (ADAR) enzymes was quantified temporally using RNA-Seq data from activated mouse macrophages to identify 342 Editing Enriched Regions (EERs), indicative of highly structured dsRNA. Nearly all mouse EERs were present in 3’UTRs. A comparison of EERs from mouse and human revealed significant conservation of EERs between mouse EER- associated genes and homologous human genes. In addition, using publicly available data and experimental validation, a significant proportion of EERs were shown to accumulate in the nucleus, a strategy that is thought to prevent aberrant activation of proinflammatory cascades in the cytoplasm. Finally, the significant conservation of EERs and the enhancement of structured regions in human suggests an increasingly important role for these regions in human biology.

ORGANISM(S): Mus musculus

PROVIDER: GSE75154 | GEO | 2016/04/14

SECONDARY ACCESSION(S): PRJNA302649

REPOSITORIES: GEO

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Identification of the long, edited dsRNAome in LPS-stimulated primary human peripheral blood monocytes

Project description:Endogenous double-stranded RNA (dsRNA) is intricately regulated in mammals to prevent aberrant activation of host inflammatory pathways by cytosolic dsRNA binding proteins. We define the endogenous dsRNA repertoire in human peripheral blood monocytes using published data (GSE60216) derived from 18 RNA-Seq experiments from neonates, adults, and elderly patients during the inflammatory response to bacterial lipopolysaccharide. Editing by adenosine deaminases that act of RNA (ADAR) enzymes was quantified temporally using this RNA-Seq data to identify 3,438 Editing Enriched Regions (EERs), indicative of highly structured dsRNA. Nearly all human EERs were present in introns. A comparison of EERs from mouse and human revealed significant conservation of EERs between mouse EER- associated genes and homologous human genes.

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ADAR1-isoforms specific editome: RNA sequencing of A-to-I editing deficient mouse embryonic fibroblast transfected with ADAR1p150 or ADAR1p110 or RFP.

Project description:Adenosine deaminase acting on RNA (ADAR) (also known as ADAR1) promotes A-to-I conversion in double-stranded and highly structured RNAs. ADAR1 has two isoforms transcribed from different promoters: ADAR1p150, which is mainly cytoplasmic and interferon-inducible, and constitutively expressed ADAR1p110 that is primarily localized in the nucleus. Mutations in ADAR1 cause Aicardi – Goutières syndrome (AGS), a severe autoinflammatory disease in humans associated with aberrant IFN production. In mice, deletion of ADAR1 or selective knockout of the p150 isoform alone leads to embryonic lethality driven by overexpression of interferon-stimulated genes. This phenotype can be rescued by concurrent deletion of cytoplasmic dsRNA-sensor MDA5. These findings indicate that the interferon-inducible p150 isoform is indispensable and cannot be rescued by the ADAR1p110 isoform. Nevertheless, editing sites uniquely targeted by ADAR1p150 but also mechanisms of isoform- specificity remain elusive. To identify ADAR1 isoform-specific ‘editome’, we transfected A-to-I editing deficient mouse embryonic fibroblasts (MEFs) with ADAR1p150- or ADAR1p110- or RFP-editing negative control. We subjected the samples to RNA sequencing and detected editing at known-editing sites.

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2014-01-07 | E-GEOD-45244 | biostudies-arrayexpress

ADAR1 utilizes independent mechanisms to suppress MDA5 and PKR activation by cellular double-stranded RNA

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2023-10-03 | GSE198386 | GEO

TDP-1, the C. elegans ortholog of TDP-43, limits the accumulation of double stranded RNA

2014-11-19 | GSE61581 | GEO

dsRNAs expressed in C. elegans development

Project description:Cellular RNAs containing double-stranded RNA (dsRNA) structures are subject to A-to-I RNA editing by the adenosine deaminases that act on RNA (ADARs). While A-to-I editing can alter mRNA coding potential, most editing is observed in non-coding sequences, the function of which remains poorly characterized. Using a dsRNA immunoprecipitation and high-thoughput sequencing (dsRIP-Seq) approach, we identify 1523 expressed A-to-I edited regions and characterize their expression during Caenorhabditis elegans development. We observe that edited regions are highly expressed in early development and are closely associated with protein-coding genes. Edited dsRNA structures give rise to abundant small interfering RNAs (siRNAs) that are negatively correlated with ADAR expression and regulate the developmental expression of associated genes.

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