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A biogenesis step upstream of Microprocessor controls miR-17~92 expression

ABSTRACT: The precise control of miR-17~92 microRNA (miRNA) is essential for normal development and overexpression of certain miRNAs from this cluster is oncogenic. Here we find the relative expression of the six miRNAs processed from the primary (pri-miR-17~92) transcript is dynamically regulated during embryonic stem cell differentiation. We identify a new miRNA biogenesis intermediate, termed ‘progenitor-miRNA’ (pro-miRNA), that is an efficient substrate for Microprocessor. An autoinhibitory 5’ RNA fragment is cleaved to generate pro-miRNA and selectively license Microprocessor-mediated production of pre-miR-17, -18a, -19a, 20a, and -19b. Using genetic, biochemical, and structural methods we define two complementary cis-regulatory repression domains required for the formation of this inhibitory RNA conformation. We find the endonuclease CPSF3 (CPSF73), and the Spliceosome-associated ISY1 are required for pro-miRNA biogenesis and expression of all miRNAs within the cluster except miR-92. Thus, developmentally regulated generation of pro-miRNA explains the posttranscriptional control of miR-17~92 expression in development.

ORGANISM(S): Mus musculus

PROVIDER: GSE68699 | GEO | 2015/05/11

SECONDARY ACCESSION(S): PRJNA283413

REPOSITORIES: GEO

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A biogenesis step upstream of Microprocessor controls miR-17~92 expression

Project description:The precise control of miR-17~92 microRNA (miRNA) is essential for normal development and overexpression of certain miRNAs from this cluster is oncogenic. Here we find the relative expression of the six miRNAs processed from the primary (pri-miR-17~92) transcript is dynamically regulated during embryonic stem cell differentiation. We identify a new miRNA biogenesis intermediate, termed ‘progenitor-miRNA’ (pro-miRNA), that is an efficient substrate for Microprocessor. An autoinhibitory 5’ RNA fragment is cleaved to generate pro-miRNA and selectively license Microprocessor-mediated production of pre-miR-17, -18a, -19a, 20a, and -19b. Using genetic, biochemical, and structural methods we define two complementary cis-regulatory repression domains required for the formation of this inhibitory RNA conformation. We find the endonuclease CPSF3 (CPSF73), and the Spliceosome-associated ISY1 are required for pro-miRNA biogenesis and expression of all miRNAs within the cluster except miR-92. Thus, developmentally regulated generation of pro-miRNA explains the posttranscriptional control of miR-17~92 expression in development. Illumina RNAseq in WT, dgcr8-/- and dicer-/- mESCs and small RNA seq in WT mESCs

2015-05-11 | E-GEOD-68699 | biostudies-arrayexpress

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Paraspeckle-Independent Co-Transcriptional Regulation of Nuclear microRNA Biogenesis by SFPQ [PRO-seq]

Project description:MicroRNAs (miRNAs) play crucial roles in physiological functions and diseases such as cancer, but the regulation of their nuclear biogenesis remains poorly understood. Here, BioID on Drosha, the catalytic subunit of the microprocessor complex, revealed its proximity to SFPQ, a multifunctional RNA-binding protein (RBP) notably involved in forming the paraspeckle nuclear condensates. SFPQ depletion impacted both primary and mature miRNA expression, while other crucial paraspeckle proteins or the paraspeckle scaffolding lncRNA NEAT1 did not, indicating a unique paraspeckle-independent role. Comprehensive transcriptomic analyses showed that SFPQ loss broadly affects RNA and miRNA host gene (miRNA HG) expression, influencing both their transcription and stability. Notably, SFPQ protects specific miRNA HGs, including the oncogenic miR-17~92 polycistron, from degradation by the nuclear NEXT-exosome complex. Lastly, we show that high SFPQ is tightly linked with overexpression miR-17~92 and its mature miRNAs across a broad variety of cancers. Our findings reveal a dual role for SFPQ in the regulation of miRNA HGs transcription and stability, as well as its significance in cancers.

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XPO5 is required for miRNA biogenesis and promotes primary miRNA processing independent of RanGTP

Project description:XPO5 mediates nuclear export of miRNA hairpin precursors in a RanGTP-dependent manner. However, the requirement of XPO5 for global miRNA biogenesis and mammalian development and XPO5-associated RNA species are not determined. Here we show that XPO5 is required for mouse embryonic development and morphogenesis of skin and brain. Loss of XPO5 compromises the biogenesis of most miRNAs and that leads to severe developmental defects. Surprisingly, XPO5 not only associates with miRNA hairpin precursors but also pervasively binds to double-stranded RNA (dsRNA) regions found in many cellular RNAs and some clustered pri-miRNAs. The binding of XPO5 to miR-17~92 pri-miRNAs is RanGTP-independent. Pre-incubation with XPO5 enhances the processing efficiency of the DROSHA/DGCR8 microprocessor. Together, our studies demonstrate the requirement of XPO5 for miRNA biogenesis and mouse development, reveal an unexpected role of XPO5 for recognizing and facilitating the nuclear cleavage of clustered pri-miRNAs and identify numerous cellular RNAs as novel XPO5 subtracts.

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Mus musculus

Project description:A biogenesis step upstream of Microprocessor controls miR-17~92 expression

| PRJNA283413 | ENA

miRNA expression in E18.5 murine total lung tissue

Project description:Knockout of the ubiquitously expressed microRNA-17~92 cluster in mice produces a lethal developmental lung defect. We validated the equally widely expressed pro-apoptotic Bim gene as joint target of miR-17~92 cluster members. To study the contribution of miR-17~92:Bim interaction to miR-17~92 overall function, we set up a system of conditional mutagenesis of the Bim 3’UTR. Blocking miR-17~92:Bim interaction early in development phenocopied the lethal lung phenotype of miR-17~92 ablation. Thus, despite hundreds of overall predicted targets vital miRNA functions can be mediated by a single target gene.

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MicroRNA biogenesis is broadly disrupted by inhibition of the splicing factor SF3B1

Project description:In animals, microRNA (miRNA) biogenesis begins with cotranscriptional cleavage of the primary (pri-)miRNA by Microprocessor. Cotranscriptional splicing has been shown to influence Microprocessor cleavage for miRNAs hosted in introns of protein coding pri-miRNAs, but the impact of splicing on production of miRNAs hosted in long noncoding (lnc)RNAs is largely unknown. Here, we investigated the role of splicing in the biogenesis of miR-122, a lncRNA-hosted, highly expressed, medically important, liver-specific miRNA. We found that splicing inhibition by the SF3B1 inhibitor Pladienolide B (PlaB) led to strong and rapid reduction in transcription of endogenous, but not plasmid-encoded, pri-miR-122, resulting in reduced production of mature miR-122. To allow detection of rapid changes in miRNA biogenesis despite the high stability of mature miRNAs, we used SLAMseq to globally quantify the effects of short-term splicing inhibition on miRNA synthesis. We observed an overall decrease in biogenesis of mature miRNAs following PlaB treatment. Surprisingly, miRNAs derived from different genomic locations were similarly affected. Together, this study provides new insight into the emerging role for splicing in transcription, demonstrating novel biological importance in promotion of miR-122 biogenesis from a lncRNA, and shows that splicing is important for global miRNA biogenesis.

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Project description:The generation of myelinating cells in the central nervous system (CNS) requires the initiation of specific gene-expression programs in oligodendrocytes. We reasoned that miRNAs could play an important role in this process by regulating critical developmental genes. Microarray profiling of cultured oligodendrocytes identifies the miR-17~92 family of miRNA cluster as highly enriched miRNAs in oligodendrocytes.We specifically deleted the miR-17~92 cluster in oligodendrocytes using the 2´3´-cyclic nucleotide 3´-phosphodiesterase (CNP)-Cre mice. Absence of miR-17~92 leads to a reduction of oligodendrocyte number in vivo and we find that the expression of these miRNAs in primary cultures of oligodendrocytes promotes cell proliferation by influencing Akt signalling. Together, these results suggest that the miRNA pathway is essential in determining oligodendroglial cell number and that the miR-17~92 cluster is crucial in this process.

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