Time-Resolved Small RNA Sequencing Unravels the Molecular Principles of MicroRNA Homeostasis

Reichholf, Brian; Herzog, Veronika A.; Fasching, Nina; Manzenreither, Raphael A.; Sowemimo, Ivica; Ameres, Stefan L.

doi:10.1016/j.molcel.2019.06.018

Cited by 133 publications

(165 citation statements)

References 82 publications

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“…This model well explains the strand ratio assessed by next generation sequencing and the magnitudes of target repression by each strand obtained from reporter assays, as recently confirmed by another group [59]. Importantly, a recent time-resolved small RNA sequencing study using thiol (SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) has provided a quantitative view of miRNA production and destruction in Drosophila S2 cells ( Figure 2c) [60]. The processing of pri-miRNAs and pre-miRNAs and generation of miRNA duplexes occurs in a matter of seconds or minutes, more rapidly than the generation of most mRNAs, and loading onto Ago proteins occurs approximately 1 h after the start of biogenesis, suggesting that Ago loading is a key bottleneck step for ensuring faithful miRNA production.…”

Section: Quantitative Features Of Mirna Biogenesis and Functionsupporting

confidence: 76%

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

Matsuyama

Suzuki

2019

IJMS

186

141

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MicroRNAs (miRNAs) are approximately 22-nucleotide-long, small non-coding RNAs that post-transcriptionally regulate gene expression. The biogenesis of miRNAs involves multiple steps, including the transcription of primary miRNAs (pri-miRNAs), nuclear Drosha-mediated processing, cytoplasmic Dicer-mediated processing, and loading onto Argonaute (Ago) proteins. Further, miRNAs control diverse biological and pathological processes via the silencing of target mRNAs. This review summarizes recent findings regarding the quantitative aspects of miRNA homeostasis, including Drosha-mediated pri-miRNA processing, Ago-mediated asymmetric miRNA strand selection, and modifications of miRNA pathway components, as well as the roles of RNA modifications (epitranscriptomics), epigenetics, transcription factor circuits, and super-enhancers in miRNA regulation. These recent advances have facilitated a system-level understanding of miRNA networks, as well as the improvement of RNAi performance for both gene-specific targeting and genome-wide screening. The comprehensive understanding and modeling of miRNA biogenesis and function have been applied to the design of synthetic gene circuits. In addition, the relationships between miRNA genes and super-enhancers provide the molecular basis for the highly biased cell type-specific expression patterns of miRNAs and the evolution of miRNA–target connections, while highlighting the importance of alterations of super-enhancer-associated miRNAs in a variety of human diseases.

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Section: Quantitative Features Of Mirna Biogenesis and Functionsupporting

confidence: 76%

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

Matsuyama

Suzuki

2019

IJMS

186

141

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“…These findings suggest that mosquito Nbr may trim pre-piRNAs generated through a Zuc-mediated endonucleolytic cut, but that only a minor fraction of such pre-piRNAs undergo trimming. Nbr-mediated trimming may be a general hallmark of aging piRNAs, as has recently been proposed for miRNAs (47). aegypti, a clear mosquito ortholog of PARN-1 can be identified: AAEL001426.…”

Section: A Subset Of Responder Pirnas Undergoes Nibbler-mediated Trimmentioning

confidence: 83%

Endogenous piRNA-guided slicing triggers responder and trailer piRNA production from viral RNA inAedes aegyptimosquitoes

Joosten

Overheul

Rij

et al. 2020

Preprint

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ABSTRACTPIWI interacting (pi)RNAs are small RNAs mostly known to protect the genomes of animal germlines against transposable elements. In Drosophila, piRNA-mediated cleavage of transposon RNA triggers the release of a responder piRNAs via the ping-pong amplification cycle. Responder piRNA 3’ end formation by the endonuclease Zucchini is coupled to the production of downstream trailer piRNAs, expanding the repertoire of piRNAs that target transposons. Intriguingly, in Aedes aegypti mosquitoes, somatic piRNAs are produced from viral RNA, implying a role of viral (v)piRNAs in antiviral immunity. Knowledge on how vpiRNA 3’ ends are formed and whether viral RNA is subjected to trailer piRNA production, however, is lacking. To address these questions, we analyzed small RNA sequencing libraries from Ae. aegypti cells. We found that virus- and transposon-derived piRNAs have sharply defined 3’ ends, and that uridine residues are enriched directly downstream of dominant piRNA sequences, both of which are characteristic features of Zucchini-like cleavage of precursor piRNAs. Next, we designed a piRNA reporter system based on Sindbis virus recombinants that harbor target sites for abundant endogenous piRNAs. These piRNAs guide cleavage of the viral RNA, which is subsequently processed into abundant responder piRNAs. Using this reporter virus system, we identified the Ae. aegypti orthologs of Zucchini, which is required for sharp 3’ end formation of responder piRNAs, and Nibbler, a 3’-5’ exonuclease involved in the trimming of a subset of piRNAs and miRNAs. Furthermore, we found that cleavage of viral RNA triggers the production of trailer piRNAs, thus expanding the piRNA sequence pool that is able to target viral RNA. Our results have important implications for understanding how autonomous piRNA production from viral RNA can be triggered by just a few cleavage events by genome-encoded piRNAs.

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“…miRNAs are found in the plasma and serum encapsulated in extracellular vesicles or bound with special lipid proteins, which make them resistant to RNase digestions ( 26 ). Several lines of evidence reported that these miRNAs have faster biogenesis and activation rates, and longer half-lives relative to mRNA and proteins, which make them suitable for detection at early stages (diagnostic), during progression or treatment selection (prognostic) ( 27 , 28 ). One of the pitfalls of using single circulatory miRNA is the lack of specificity.…”

Section: Aberrant Expression Of Mirnas: Potential Diagnostic and Progmentioning

confidence: 99%

Roles of microRNAs in Ovarian Cancer Tumorigenesis: Two Decades Later, What Have We Learned?

Alshamrani

2020

Front. Oncol.

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Ovarian cancer is one of the top gynecological malignancies that cause deaths among females in the United States. At the molecular level, significant progress has been made in our understanding of ovarian cancer development and progression. MicroRNAs (miRNAs) are short, single-stranded, highly conserved non-coding RNA molecules (19–25 nucleotides) that negatively regulate target genes post-transcriptionally. Over the last two decades, mounting evidence has demonstrated the aberrant expression of miRNAs in different human malignancies, including ovarian carcinomas. Deregulated miRNAs can have profound impacts on various cancer hallmarks by repressing tumor suppressor genes. This review will discuss up-to-date knowledge of how the aberrant expression of miRNAs and their targeted genes drives ovarian cancer initiation, proliferation, survival, and resistance to chemotherapies. Understanding the mechanisms by which these miRNAs affect these hallmarks should allow the development of novel therapeutic strategies to treat these lethal malignancies.

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Time-Resolved Small RNA Sequencing Unravels the Molecular Principles of MicroRNA Homeostasis

Cited by 133 publications

References 82 publications

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis

Endogenous piRNA-guided slicing triggers responder and trailer piRNA production from viral RNA inAedes aegyptimosquitoes

Roles of microRNAs in Ovarian Cancer Tumorigenesis: Two Decades Later, What Have We Learned?

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