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Transcriptomic profiling of HEK293 cells upon individual knockdown of the splicing factors RBM17, U2SURP or CHERP

ABSTRACT: We found that the core spliceosomal proteins RBM17, U2SURP and CHERP form a protein complex regulating alternative splicing and expression of a whole network of RNA binding proteins

ORGANISM(S): Homo sapiens

PROVIDER: GSE107648 | GEO | 2018/10/17

REPOSITORIES: GEO

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transcriptomic profiling of HEK293 cells upon individual knockdown of the splicing factors RBM17, U2SURP or CHERP

Project description:transcriptomic profiling of HEK293 cells upon individual knockdown of the splicing factors RBM17, U2SURP or CHERP

| PRJNA420970 | ENA

RBM17 Mediates Evasion of Pro-Leukemic Factors from Splicing-coupled NMD to Enforce Leukemic Stem Cell Maintenance

Project description:Acute myeloid leukemia (AML) patients suffer from chemo-resistance, high relapse frequency, and low overall survival rate, outcomes driven by leukemic stem cells (LSCs). Understanding the molecular mechanisms that support these primitive leukemic cells is crucial for developing effective AML therapeutics. In the present study, we demonstrate that upregulation of the splicing factor RBM17 preferentially marks and sustains the primitive compartment of AML. RBM17 expression is significantly higher in LSCs and its levels in human AML directly correlate with shortened survival in patients with the disease. RBM17 knockdown in primitive primary AML cells leads to myeloid differentiation and the impairment of their in vitro colony forming and in vivo engraftment capacities. To study the molecular mechanisms underlying the functional roles of RBM17 in AML, we performed global profiling of the RBM17-RNA interactome and proteome changes downstream of RBM17 knockdown. Through these integrative multi-omics analyses, we show that RBM17 repression leads to inclusion of poison exons and production of nonsense-mediated decay (NMD)-sensitive transcripts for pro-leukemic factors such as RBM39 and EZH2, along with the translation initiation factor EIF4A2. We further show that EIF4A2 expression is enriched in LSCs and inhibition of EIF4A2 impairs primary AML progenitor activity. Proteome analysis of AML cells after EIF4A2 knockdown demonstrate that EIF4A2 repression largely recapitulates the biological effect of RBM17 knockdown including the pronounced suppression of proteins involved in ribosome biogenesis. Overall, these results provide a rationale to target RBM17 and/or its downstream NMD-sensitive splicing substrates in primitive leukemic cells for AML treatment.

2022-04-26 | GSE180955 | GEO

Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models

Project description:Translating ribosome affinity purification technology was used to isolate mRNAs from cerebellar Purkinje neurons from control (Pcp2-BacTrap; Rbm17 f/+) and mutant (Pcp2-BacTRAP; Pcp2-Cre; Rbm17 f/-) mice.

2016-10-28 | GSE79020 | GEO

CHERP controls alternative mRNA splicing in human cell line

Project description:Calcium Homeostasis Endoplasmic Reticulum Protein (CHERP) is co-localized with inositol 1,4,5-trisphosphate receptor (IP3R) in the endoplasmic reticulum or peri-nuclear part, and has been considered to have a role in intracellular calcium signaling. Recently, it has recognized that CHERP structurally carries nuclear localization signal and arginine/serine-dipeptide repeats like domain, and interacts with spliceosome. In this study, we showed that poly (A)+ RNA was accumulated in the nucleus on CHERP depletion. Using the global analysis, CHERP regulated alternative mRNA splicing events through the interaction with U2 snRNP and U2 snRNP related proteins. Our analysis indicated that intron retention was most frequently observed among five alternative splicing patterns in accordance with the accumulation of poly (A)+ RNA in the nucleus. Further, intron retention and cassette exon choice were influenced by the strength of 5’ or 3’ splice site, GC content, or intron length. In addition, CHERP depletion induced the abnormality of cell cycle progression at M phase and cell division. These results suggested that CHERP was involved in the regulation of alternative splicing.

2022-06-19 | GSE193399 | GEO

Rbm17 complex identification from mouse brain

Project description:Here we characterized a splicesomal sub-complex including the proteins RBM17, U2SURP and CHERP, and found that these proteins physically interact and regulate reciprocal posttranslational stability; individually knocked down, they cause widely overlapping and consistent splicing and gene expression changes of transcripts enriched for RNA processing factors.

2017-12-04 | MSV000081776 | MassIVE

Alternative splicing regulation of cell cycle genes by SPF45/SR140/CHERP complex controls cancer cell proliferation

Project description:SPF45, SR140 and CHERP were knock downed using lentiviral delivery of shRNAs in HeLa cells

2021-07-30 | GSE180892 | GEO

Determination of genome-wide splicing patterns in Huh-7 cells upon knockdown of spliceosomal targets

Project description:Key U2 spliceosomal proteins and their interactors were knocked down in Huh-7 cells and the subsequent changes in pre-mRNA splicing were detected by RNASeq

| PRJEB46899 | ENA

Impact of LARP7 depletion on the pA+ transcriptome of HEK293 cells upon heat shock

Project description:The La-related protein LARP7 has been mainly described as a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, which negatively regulates RNA polymerase II by sequestering the positive transcription elongation factor b (P-TEFb). In our studies, we discovered a novel, 7SK snRNP-independent function of LARP7. We show that LARP7 interacts with the U6 spliceosomal RNA as well as with the small nucleolar RNAs (snoRNAs) directing the 2'-O-methylations of U6. Importantly, in the absence of LARP7, significantly less 2'-O-methylations are deposited on U6 affecting splicing fidelity. Mutations in the LARP7 gene have been associated with the Alazami syndrome, a form of primary dwarfism characterized by intellectual disability. We describe a novel loss-of-function mutation of LARP7 occurring in Alazami patients and detect reduced 2'-O-methylations of U6 in patient-derived samples. Thus, aberrant posttranscriptional RNA modifications of the spliceosomal U6 snRNA may contribute to the development of this severe disease.

2020-02-03 | GSE134813 | GEO

HMJSL C. Neoformans splicing factor knockout RNA-seq

Project description:We determined that over 60 spliceosomal proteins are conserved between many fungal species and humans but were lost during the evolution of S. cerevisiae, an intron-poor yeast with unusually rigid splicing signals. We analyzed null mutations in a subset of these factors, most of which had not been investigated previously, in the intron-rich yeast Cryptococcus neoformans. We found they govern splicing efficiency of introns with divergent spacing between intron elements. Importantly, most of these factors also suppress usage of weak nearby cryptic/alternative splice sites. Among these, orthologs of GPATCH1 and the helicase DHX35 display correlated functional signatures and copurify with each other as well as components of catalytically active spliceosomes, identifying a conserved G-patch/helicase pair that promotes splicing fidelity. We propose that a significant fraction of spliceosomal proteins in humans and most eukaryotes are involved in limiting splicing errors, potentially through kinetic proofreading mechanisms, thereby enabling greater intron diversity.

2021-03-13 | GSE168814 | GEO

The conserved ubiquitin-like protein Hub1 plays a critical role in splicing in human cells

Project description:Different from canonical ubiquitin-like proteins, Hub1 does not form covalent conjugates with substrates but binds proteins non-covalently. In Saccharomyces cerevisiae, Hub1 associates with spliceosomes and mediates alternative splicing of SRC1, without affecting pre-mRNA splicing generally. Human Hub1 is highly similar to its yeast homolog, but its cellular function remains largely unexplored. Here, we show that human Hub1 binds to the spliceosomal protein Snu66 as in yeast, however, unlike its S. cerevisiae homolog, human Hub1 is essential for viability. Prolonged in vivo depletion of human Hub1 leads to various cellular defects, including splicing speckle abnormalities, partial nuclear retention of mRNAs, mitotic catastrophe and consequently cell death by apoptosis. Early consequences of Hub1 depletion are severe splicing defects, however, only for specific splice sites leading to exon skipping and intron retention. Thus, the ubiquitin-like protein Hub1 is not a canonical spliceosomal factor needed generally for splicing, but rather a modulator of spliceosome performance and facilitator of alternative splicing. Human U2OS cells were transfected with siRNAs to specifically knockdown the ubiquitn-like protein Hub1. Cells treated with non-targeting oligos (GL2) served as negative control. Total RNAs of three biological replicates of each knockdown experiment were isolated and changes of splicing patterns were subsequently analyzed by Affymetrix GeneChip Human Exon 1.0 ST arrays

2014-05-30 | E-GEOD-56878 | biostudies-arrayexpress

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