Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Acetylation of spliceosome protein PHF5A modulates stress responses and colorectal carcinogenesis through alternative splicing mediated upregulation of KDM3A

ABSTRACT: The process utilized by cancer cells for adapting to cellular stress is a key point for carcinogenesis. Alternative pre-mRNA splicing induced post-transcriptional gene expression regulation is one of the pathways for tumors maintaining proliferation rates accompanying the malignant phenotype under stress. However, the protein post-translational modification, especially protein acetylation on pre-mRNA splicing processes under stress is unknown. Here, we uncovered a list of hyperacetylated proteins in the context of acutely reduced Acetyl-CoA levels under nutrient starvation. PHD finger-like domain-containing protein 5A (PHF5A/SF3b14b), a component of U2 snRNPs, can be acetylated at lysine 29 in response to multiple cellular stresses. P300 and HDAC6 regulate PHF5A acetylation levels. PHF5A acetylation strengthens the interaction among U2 snRNPs, and affects global pre-mRNA splicing pattern and extensive gene expression. PHF5A hyperacetylation induced alternative splicing stabilizes KDM3A mRNA and promotes its protein expression. Pathologically, PHF5A K29 hyperacetylation and KDM3A upregulation axis are correlated with poor prognosis of colon cancer patients. Our findings uncovered a novel mechanism of anti-stress pathway that acetylation on PHF5A promotes the cancer cells capacity for stress resistance and consequently contributes to colon carcinogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE122761 | GEO | 2018/11/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcriptome-wide identification of transcripts regulated by PHF5A in colorectal cancer cells

Project description:Dysregulated alternative splicing (AS) plays critical roles in driving cancer progression, and the underlying mechanisms remain largely unknown. Here we demonstrated that PHF5A, a component of U2 snRNPs, was frequently upregulated in colorectal cancer (CRC) samples and associated with poor prognosis. PHF5A promoted proliferation and metastasis of CRC cells in vitro and in vivo. Transcriptomic analysis identified PHF5A-regulated AS targets and pathways. Particularly, PHF5A induced TEAD2 exon 2 inclusion to activate YAP signaling, and interference of TEAD2-L partially reversed the PHF5A-mediated tumor progression. Pharmacological inhibition of PHF5A using pladienolide B had potent antitumor activity. Collectively, these data revealed the oncogenic role of PHF5A in CRC through regulating AS, and established PHF5A as potential therapeutic target.

2021-07-16 | GSE180042 | GEO

Arabidopsis SME interactome reveals spliceosome components

Project description:Alternative splicing (AS) can produce multiple transcripts with different exon-intron structures from a single pre-mRNA. Pre-mRNA splicing is catalyzed by a dynamic macromolecular ribonucleoprotein (RNP) complex termed the spliceosome. The spliceosome consists of several small nuclear ribonucleoproteins (snRNPs) that bind uridine-rich small nuclear RNA (snRNA). In U1, U2, U4 and U5 snRNPs, snRNA interacts with the conserved Smith antigen (Sm) proteins via a bipartite Sm sequence motif. In eukaryotes, seven Sm proteins (B, D1/2/3, E, F and G) form a heptameric ring-shaped complex surrounding the snRNA. Here, we performed a tandem affinity purification using SMEB as a bait in Arabidopsis cell suspension cultures. At least 45 known/hypothesized and potential novel spliceosome components were identified in Arabidopsis.

2023-03-03 | PXD016607 | Pride

Transcriptome changes in splicing inhibited cells

Project description:In eukaryotes, U1 small nuclear ribonucleoprotein (snRNP) forms spliceosomes in equal stoichiometry with U2, U4, U5 and U6 snRNPs; however, its abundance in human far exceeds that of the other snRNPs. Here we used antisense morpholino oligonucleotide to U1 snRNA to achieve functional U1 snRNP knockdown in HeLa cells, and identified accumulated unspliced pre-mRNAs by genomic tiling microarrays. In addition to inhibiting splicing, U1 snRNP knockdown caused premature cleavage and polyadenylation in numerous pre-mRNAs at cryptic polyadenylation signals, frequently in introns near (<5 kilobases) the start of the transcript. This did not occur when splicing was inhibited with U2 snRNA antisense morpholino oligonucleotide or the U2-snRNP-inactivating drug spliceostatin A unless U1 antisense morpholino oligonucleotide was also included. We further show that U1 snRNA–pre-mRNA base pairing was required to suppress premature cleavage and polyadenylation from nearby cryptic polyadenylation signals located in introns. These findings reveal a critical splicing-independent function for U1 snRNP in protecting the transcriptome, which we propose explains its overabundance.

2010-09-29 | GSE24179 | GEO

Global analysis of binding sites of SF3B1 by CLIP-seq

Project description:SF3B1 is one of shared components of U2 and U12 snRNPs that are required for splicing of U2-type and U12-type introns, respectively. Interestingly, recurrent somatic mutations have been identified in the spliceosome components in human cancer. By using CLIP-seq for SF3B1, binding sites in human embryonic stem cells were determined. The most prominent binidng sites were at 3' splice sites on pre-mRNA. Interestingly, 5' and 3' ends of introns spliced out were enriched by CLIP.

2023-04-26 | GSE222867 | GEO

Overlapping roles of spliceosomal components SF3B1 and PHF5A in rice splicing regulation

Project description:The SF3B complex, a multiprotein component of the U2 snRNP of the spliceosome, mediates branch point selection and facilitates spliceosome assembly and activation. Several splicing modulators bind the SF3B1 and PHF5A subunits of the SF3B complex and globally inhibit splicing. Engineered mutant variants of SF3B1 and PHF5A conferred tolerance to splicing inhibitors with only minor effects on gene expression and AS.

2021-04-11 | GSE153234 | GEO

The histone variant H2A.Z promotes efficient co-transcriptional splicing in S. cerevisiae

Project description:In eukaryotes, a dynamic ribonucleic protein machine known as the spliceosome catalyzes the removal of introns from pre-messenger RNA (pre-mRNA). Recent studies show the process of RNA-synthesis and RNA-processing to be spatio-temporally coordinated, indicating that RNA splicing takes place in the context of chromatin. H2A.Z is a highly conserved histone variant of the canonical histone H2A. In S. cerevisiae, H2A.Z is deposited into chromatin by the SWR1-complex, is found near the 5’ ends of protein-coding genes, and has been implicated in transcription regulation. Here we show that splicing of intron-containing genes in cells lacking H2A.Z is impaired, particularly under suboptimal splicing conditions. Cells lacking H2A.Z are especially dependent on a functional U2 snRNP, as H2A.Z shows extensive genetic interactions with U2 snRNP associated proteins, and RNA-seq reveals introns with non-consensus branch points are particularly sensitive to H2A.Z loss. Consistently, H2A.Z promotes efficient spliceosomal rearrangements involving the U2 snRNP, as H2A.Z loss results in persistent U2 snRNP association and decreased recruitment of downstream snRNPs to nascent RNA. H2A.Z impairs transcription elongation, suggesting that spliceosome rearrangements are tied to H2A.Z’s role in elongation. Depletion of disassembly factor Prp43 suppresses H2A.Z-mediated splice defects, indicating that, in the absence of H2A.Z, stalled spliceosomes are disassembled and unspliced RNAs are released. Together these data demonstrate that H2A.Z is required for efficient pre-mRNA splicing and indicate a role for H2A.Z in coordinating the kinetics of transcription elongation and splicing.

2017-05-18 | GSE97416 | GEO

PHF5A coordinates p300 for epigenetic regulation of lipogenesis to promote hepatocellular carcinoma progression

Project description:PHD-finger protein 5A (PHF5A) is a component of U2snRNP, which plays a critical role in mRNA splicing for recognizing the branch site. However, whether it also plays other functions independent of RNA splicing remains elusive. Here, we find that expression levels of PHF5A are significantly upregulated in hepatocellular carcinoma (HCC). Down-regulation of PHF5A restrains liver cancer cell proliferation in vitro and in vivo. RNA-sequencing analysis reveals that fatty-acid biosynthetic enzymes are major downstream targets of PHF5A in HCC. Through metabolomics analysis, we find that inhibition of PHF5A reduces free fatty acid and phospholipid synthesis, further suppressing plasma membrane function. Mechanistically, PHF5A acts as a transcription co-factor of the p300 acetyltransferase for the H3K27 acetylation (Ac) and promotes H3K27Ac-dependent lipogenic genes expression. Our findings demonstrated a surprising splicing-independent role of PHF5A in transcriptional regulation of lipid metabolism for HCC progression and provided a new strategy for HCC therapy by blocking the interaction of PHF5A and p300.

2021-10-01 | GSE167023 | GEO

Acetylation of spliceosome protein PHF5A modulates stress responses and colorectal carcinogenesis through alternative splicing mediated upregulation of KDM3A

Project description:Acetylation of spliceosome protein PHF5A modulates stress responses and colorectal carcinogenesis through alternative splicing mediated upregulation of KDM3A

| PRJNA506256 | ENA

A single SR-like protein, Npl3, promotes pre-mRNA splicing in budding yeast

Project description:Mammalian SR proteins are a family of reversibly phosphorylated RNA binding proteins primarily studied for their roles in alternative splicing. While budding yeast lack alternative splicing, they do have three SR-like proteins: Npl3, Gbp2, and Hrb1. However, these have been primarily studied for their roles in mRNA export, leaving their potential roles in splicing largely unexplored. Here we combined high-density genetic interaction profiling and genome-wide splicing-sensitive microarray analysis to demonstrate that a single SR-like protein, Npl3, is required for efficient splicing of a large set of pre-mRNAs in Saccharomyces cerevisiae. We tested the hypothesis that Npl3 promotes splicing by facilitating co-transcriptional recruitment of splicing factors. Using chromatin immunoprecipitation, we showed that mutation of NPL3 reduces the occupancy of U1 and U2 snRNPs at Npl3-stimulated genes. This provides the first evidence that an SR protein can promote recruitment of splicing factors to chromatin.

2008-12-31 | GSE11491 | GEO

Transcriptome changes in spliceostatin A treated cells

Project description:Pre-mRNA in eukaryotes is subjected to post-transcriptional modifications, such as capping, polyadenylation and splicing. It is well known that transcription and post-transcriptional modifications are coupled and that this coupling stimulates post-transcriptional modifications, however, the effects of post-transcriptional modifications on transcription are not fully understood. Here, we report that inhibition of U2 snRNP by a splicing inhibitor, spliceostatin A (SSA), and antisense morpholino oligonucleotide to U2 snRNA caused 3’ end down regulation in a gene-specific manner. We also show that U2 snRNP inhibition resulted in the dephosphorylation of second serine residues (Ser2) within heptad repeats of the C-terminal domain (CTD) of Pol II, which is important for transcription elongation, and this dephosphorylation was correlated with splicing inactivation. Interestingly, removal of SSA from the culture media caused restoration of the Ser2 phosphorylation and expression of the 3’ end, suggesting that transcription elongation resumed. These findings suggest that a novel checkpoint mechanism prevents pre-mRNA accumulation and the production of aberrant proteins translated from pre-mRNA upon splicing deficiencies through the dephosphorylation of CTD Ser2. Treated HeLa cells with methanol or spliceosotain A for 3 hours followed by labelling of nascent transcripts with EU for 1 hour. The EU labelled nascent RNA was purified and analyzed on human exon 1.0ST array. Three biological replicates were used for each treatment.

2013-03-28 | E-GEOD-45379 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data