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Genome wide mapping of effects of U6atac knockdown on pre-mRNA splicing

ABSTRACT: This project looks into experimentally identifying all minor introns by knocking down the minor spliceosome's catalytic snRNP, U6atac. Knockdown of U6atac by antisense morpholino followed by examining mRNA splicing by RNA-seq

ORGANISM(S): Homo sapiens

SUBMITTER: Ihab Younis

PROVIDER: E-GEOD-48263 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Minor introns are embedded molecular switches regulated by highly unstable U6atac snRNA.

Younis Ihab I Dittmar Kimberly K Wang Wei W Foley Shawn W SW Berg Michael G MG Hu Karen Y KY Wei Zhi Z Wan Lili L Dreyfuss Gideon G

eLife 20130730

Eukaryotes have two types of spliceosomes, comprised of either major (U1, U2, U4, U5, U6) or minor (U11, U12, U4atac, U6atac; <1%) snRNPs. The high conservation of minor introns, typically one amidst many major introns in several hundred genes, despite their poor splicing, has been a long-standing enigma. Here, we discovered that the low abundance minor spliceosome's catalytic snRNP, U6atac, is strikingly unstable (t½<2 hr). We show that U6atac level depends on both RNA polymerases II and III an ...[more]

PMID: 23908766

Similar Datasets

Genome wide mapping of effects of U6atac knockdown on pre-mRNA splicing

Project description:This project looks into experimentally identifying all minor introns by knocking down the minor spliceosome's catalytic snRNP, U6atac.

2013-08-01 | GSE48263 | GEO

Frac-seq reveals preferential polyribosome association of minor mRNA isoforms

Project description:The goal of this study was to test the hypothesis that minor alternative mRNA isoforms can be preferentially translated. Included are Cytoplasm and Polyribosome samples in duplicate from both Control and Rapamycin treated cells.

2013-06-13 | E-GEOD-45237 | biostudies-arrayexpress

Distinct functions for the paralogous RBM41 and U11/U12-65K proteins in the minor spliceosome

Project description:We identify RBM41 as a novel unique protein component of the minor spliceosome. RBM41 has no previously recognized cellular function but has been identified as a paralog of the U11/U12-65K protein, a known unique component of the minor spliceosome that functions during the early steps of minor intron recognition as a component of the U11/U12 di-snRNP. We show that both proteins use their highly similar C-terminal RRMs to bind to 3'-terminal stem-loops in U12 and U6atac snRNAs with comparable affinity. Our BioID data indicate that the unique N-terminal domain of RBM41 is necessary for its association with complexes containing DHX8, an RNA helicase, which in the major spliceosome drives the release of mature mRNA from the spliceosome. Consistently, we show that RBM41 associates with excised U12-type intron lariats, is present in the U12 mono-snRNP, and is enriched in Cajal bodies, together suggesting that RBM41 functions in the post-splicing steps of the minor spliceosome assembly/disassembly cycle. This contrasts with the U11/U12-65K protein, which uses the N-terminal region to interact with U11 snRNP during the intron recognition step. Finally, we show that while RBM41 knockout cells are viable, they show alterations in the splicing of U12-type introns, particularly differential U12-type 3' splice site usage. Together, our results highlight the role 3’-terminal stem-loop of U12 snRNA as a dynamic binding platform for the paralogous U11/U12-65K and RBM41 proteins, which function at distinct stages of minor spliceosome assembly/disassembly cycle.

2024-02-04 | GSE246283 | GEO

U1 snRNP telescripting regulates size-function stratified human genome

Project description:This project looks into how U1 snRNP inhibition causes a loss of telescripting through premature cleavage and polyadenylation based on the size and function of human genes.

2017-10-02 | GSE103252 | GEO

Functional divergence of the paralogous RBM41 and U11/U12-65K proteins in the minor spliceosome

Project description:In this work, we identify RBM41 as a novel unique protein component of the minor spliceosome. RBM41 has no previously recognized cellular function but has been identified as a paralog of the U11/U12-65K protein, a known unique component of the minor spliceosome that functions during the early steps of minor intron recognition as a component of the U11/U12 di-snRNP. We show that both proteins use their highly similar C-terminal RRMs to bind to 3'-terminal stem-loops in U12 and U6atac snRNAs with comparable affinity. Our BioID data indicate that the unique N-terminal domain of RBM41 is necessary for its association with complexes containing DHX8, an RNA helicase, which in the major spliceosome drives the release of mature mRNA from the spliceosome.

| MSV000092983 | MassIVE

miR-126 Orchestrates an Oncogenic Program in B-Cell Precursor Acute Lymphoblastic Leukemia

Project description:MicroRNA (miRNA)-126 is a known regulator of hematopoietic stem cell quiescence. We engineered murine hematopoiesis to express miRNA-126 across all differentiation stages. Thirty percent of mice developed monoclonal B cell leukemia, which was prevented or regressed when a tetracycline-repressible miRNA-126 cassette was switched off. Regression was accompanied by upregulation of cell-cycle regulators and B cell differentiation genes, and downregulation of oncogenic signaling pathways. Expression of dominant-negative p53 delayed blast clearance upon miRNA-126 switch-off, highlighting the relevance of p53 inhibition in miRNA-126 addiction. Forced miRNA-126 expression in mouse and human progenitors reduced p53 transcriptional activity through regulation of multiple p53-related targets. miRNA-126 is highly expressed in a subset of human B-ALL, and antagonizing miRNA-126 in ALL xenograft models triggered apoptosis and reduced disease burden. Study 1: Turning off miR-126 expression from an experimental murine B-ALL in vivo; Study 2: Modulation of miR-126 expression in human cord blood stem and progenitor cell populations in vitro.

2016-06-14 | E-GEOD-78078 | biostudies-arrayexpress

Minor intron splicing efficiency increases with the development of lethal prostate cancer

Project description:Minor intron-containing genes (MIGs) are crucial cell cycle regulators and are essential for cell survival. Thus, we explored whether MIGs play a role in cancer progression and cancer therapy resistance. Here we show that MIG-expression segregates sensitive and resistant prostate cancer cells from each other and them from benign tissue. Moreover, the rate of minor intron splicing, a crucial regulatory node for MIG-expression, was more efficient in patients with advanced prostate cancer. We show that the increased minor spliceosome (MiS) activity is downstream of the androgen receptor signaling axis in both therapy sensitive and insensitive prostate cancer types. The increased MiS activity was in line with the elevated expression of U6atac snRNA, a crucial MiS component. We propose the expression of U6atac as a potential point of vulnerability in cancer. MIGs are uniquely susceptible to the MiS, so we used siRNA against U6atac, which like protein-coding transcripts, is downregulated. Inhibition of MiS was sufficient to lower the tumor burden significantly in therapy-resistant (prostate) cancer cells and PCa patient-derived organoids. KD cells displayed elevated minor intron retention and alternative splicing across minor introns of MIGs which enriched for MAPK activity, DNA repair and cell cycle regulation. Importantly, these findings were confirmed by MassSpec analysis. Collectively our study nominates the MiS as a driver of highly proliferative, rapidly dividing (prostate) cancer cells that bears strong potential as a therapeutic target for many different cancer types.

2023-06-08 | PXD026949 | Pride

Minor intron splicing efficiency increases with the development of lethal prostate cancer

Project description:We sought to determine the effect of a minor spliceosome inhibition by U6atac snRNA depletion in prostate cancer. We performed siRNA-mediated knock-down (96h) of the minor spliceosome snRNA U6atac in androgen-sensitive LNCaP cells, androgen-insensitive C4-2 and 22Rv1 cells and in patient derived neuroendocrine organoids (PM154). We compared global transcriptional alterations and lineage dependency using RNA-seq and scRNAseq.

| EGAS00001005546 | EGA

human 3' RACE

Project description:Mpn1 proteins are evolutionarily conserved exonucleases that modify spliceosomal U6 small nuclear RNAs (snRNAs) post-transcriptionally. Mutations in the human MPN1 gene are associated to the genodermatosis Clericuzio-type poikiloderma with neutropenia (PN). Mpn1 deficiency leads to aberrant U6 3M-bM-^@M-^Y end processing and accelerated U6 decay through unknown molecular mechanisms. Here we show that in mpn1M-NM-^T fission yeast cells U6 is barely bound by the protective Lsm2-8 complex, undergoes extensive oligoadenylation and is degraded by the nuclear RNA exonuclease Rrp6 independently of the poly(A) polymerase Cid14/Trf4. Mpn1 processes U6 in a spliceosome-dependent manner, as mutant U6 molecules that fail to join the spliceosome are not substrates for Mpn1. Moreover, human U6atac, the U6-like snRNA of the minor spliceosome, is a novel substrate for hMpn1. We unveil mechanistic details of a new U6 degradation pathway and further corroborate the notion that inefficient canonical and minor pre-mRNA splicing promotes PN. the 3' termini of human U6, U6atac and vtRNA1-1 transcripts from PN patient derived cells and from PN patient cells, compensated with hMPN1 were sequenced.

2014-08-08 | E-GEOD-60196 | biostudies-arrayexpress

Defective minor spliceosomes induce SMA-associated phenotypes through sensitive intron-containing neural genes in Drosophila

Project description:The minor spliceosome is evolutionarily conserved in higher eukaryotes, but its biological significance remains poorly understood. Here, by precise CRISPR/Cas9-mediated disruption of the U12 and U6atac snRNAs, we report that a defective minor spliceosome is responsible for spinal muscular atrophy (SMA) associated phenotypes in Drosophila. Using a newly developed bioinformatic approach, we identified a large set of minor spliceosome-sensitive splicing events and demonstrate that three sensitive intron-containing neural genes, Pcyt2, Zmynd10, and Fas3, directly contribute to disease development as evidenced by the ability of their cDNAs to rescue the SMA-associated phenotypes in muscle development, neuromuscular junctions, and locomotion. Interestingly, many splice sites in sensitive introns are recognizable by both minor and major spliceosomes, suggesting a new mechanism of splicing regulation through competition between minor and major spliceosomes. These findings reveal a vital contribution of the minor spliceosome to SMA and to regulated splicing in animals.

2020-04-01 | GSE138183 | GEO

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