Decreased SRSF7 expression induces cellular senescence via generating MDM2 variants
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA961140 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24293479_1.fastq.gz | Fastqsanger.gz | |||
| SRR24293479_2.fastq.gz | Fastqsanger.gz | |||
| SRR24293480_1.fastq.gz | Fastqsanger.gz | |||
| SRR24293480_2.fastq.gz | Fastqsanger.gz | |||
| SRR24293481_1.fastq.gz | Fastqsanger.gz |
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Project description:To evaluate the role of alternative splicing in cellular senescence, we analyzed transcriptomics by RNAseq in SRSF3 and SRSF7 suppressed human diploid fibroblasts.
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Project description:Alternative splicing (AS) enables a pre-mRNA to generate different functional protein variants. The change in AS has been reported as an emerging contributor to cellular senescence and aging. However, it remains to be elucidated which senescent AS variants are generated in and regulate senescence. Here, we observed commonly down-regulated SRSF7 in senescent cells, using publicly available RNA-seq datasets of several in vitro senescence models. We further confirmed SRSF7 deregulation from our previous microarray datasets of time-series replicative senescence (RS) and oxidative stress-induced senescence (OSIS) of human diploid fibroblast (HDF). We validated the time-course changes of SRSF mRNA and protein levels, developing both RS and OSIS. SRSF knockdown in HDF was enough to induce senescence, accompanied by p53 protein stabilization and MDM2 variants formation. Interestingly, expression of MDM2 variants showed similar patterns of p53 expression in both RS and OSIS. Next, we identified MDM2-C as a key functional AS variant generated specifically by SRSF7 depletion. Finally, we validated that MDM2-C overexpression induced senescence of HDF. These results indicate that SRSF7 down-regulation plays a key role in p53-mediated senescence by regulating AS of MDM2, a key negative regulator of p53, implying its critical involvement in the entry into cell senescence.
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Project description:We used P19 cells that overexpress GFP-tagged SRSF7 by 3.4-fold and expression-matched SRSF7 mutants that either lack a functional Zinc-knuckle domain or a part of their RS-domain and compared the extent and pattern of binding to mRNAs. For this we performed iCLIP using anti-GFP antibodies. We also performed iCLIP from monosomal and polysomal fractions. In addition we performed iCLIP using anti-SRSF7 antibodies to compare the binding patterns of SRSF7-GFP, endogenous SRSF7 protein and its truncated SRSF7_RRM variant.
2020-03-02 | GSE140721 | GEO
Project description:RNA seq was performed after IP of Ab-SRSF7 in Huh7 cells.
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Project description:Alternative polyadenylation (APA) refers to the regulated selection of polyadenylation sites (PASs) in transcripts, which determines the length of their 3’ untranslated regions (3’UTRs). APA regulates stage- and tissue-specific gene expression by affecting the stability, subcellular localization and translation rate of transcripts. We have recently shown that SRSF3 and SRSF7, two closely related SR proteins, connect APA with mRNA export. The mechanism underlying APA regulation by SRSF3 and SRSF7 remained, however, unknown. Here, we combined iCLIP, RNA-Seq and 3’-end sequencing to find that both proteins bind upstream of proximal PASs (pPASs), yet they exert opposite effects on 3’UTR length. We show that SRSF7 enhances pPAS usage in a concentration-dependent but splicing-independent manner by recruiting the cleavage factor FIP1, thereby generating short 3’UTRs. Protein domains unique to SRSF7, which are absent from SRSF3, and hypo-phosphorylation contribute to FIP1 recruitment. In contrast, SRSF3 promotes distal PAS (dPAS) usage and hence long 3’UTRs by maintaining high levels of cleavage factor Im (CFIm) via alternative splicing. Upon reduced expression of SRSF3, CFIm levels strongly decrease and 3’UTRs are globally shortened. In SRSF3-regulated transcripts, CFIm and FIP1 bind upstream of dPASs and promote their usage. Surprisingly, both factors are also recruited to pPASs under conditions where their usage is blocked, suggesting the formation of inactive cleavage complexes. Thus, we identify SRSF3 as a novel regulator of CFIm activity, provide evidence that CFIm inhibits pPAS usage and show that small differences in the domain architecture of SR proteins confer opposite effects on PAS selection.
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Project description:Heat shock transcription factor 1 (HSF1) regulates the expression of a wide array of genes, controlling expression of heat shock proteins (HSPs) and cell growth. Although acute depletion of HSF1 induces cellular senescence, the underlying mechanisms are poorly understood. Here, we report that HSF1 depletion-induced senescence (HDIS) of human diploid fibroblasts (HDFs) was independent of HSP-mediated proteostasis, but dependent on activation of the p53-p21 pathway, partly because of increased expression of dehydrogenase/reductase 2 (DHRS2), a putative MDM2 inhibitor. We observed that HDIS occurred without decreased levels of major HSPs or increased proteotoxic stress in HDFs. Additionally, an inhibitor of HSP70 family proteins increased proteotoxicity and suppressed cell growth, but failed to induce senescence. Importantly, we found that activation of the p53-p21 pathway due to reduced MDM2-dependent p53 degradation was required for HDIS. Furthermore, we provide evidence that increased DHRS2 expression contribute to p53 stabilization and HDIS. Collectively, our observations uncovered a molecular pathway in which HSF1 depletion-induced DHRS2 expression leads to activation of the MDM2-p53-p21 pathway required for HDIS.
2018-05-01 | GSE111355 | GEO
Project description:Alternative polyadenylation (APA) refers to the regulated selection of polyadenylation sites (PASs) in transcripts, which affects the length of their 3’ untranslated regions (3’UTRs). APA regulates stage- and tissue-specific gene expression by affecting the stability, subcellular localization or translation rate of transcripts. We have recently shown that SRSF3 and SRSF7, two closely related SR proteins, link APA to mRNA export. However, the underlying mechanism for APA regulation by SRSF3 and SRSF7 remained unknown. Here, we combined iCLIP and 3’-end sequencing to find that both proteins bind upstream of proximal PAS (pPAS), but exert opposing effects on 3’UTR length. We show that SRSF7 enhances pPAS usage in a splicing-independent and concentration-dependent manner by recruiting the cleavage factor FIP1, thereby generating short 3’UTRs. SRSF7-specific domains that are absent in SRSF3 are necessary and sufficient for FIP1 recruitment. SRSF3 promotes long 3’UTRs by maintaining high levels of the cleavage factor Im (CFIm) via alternative splicing. Using iCLIP, we show that CFIm binds before and after the pPASs of SRSF3 targets, which masks them and inhibits polyadenylation. In the absence of SRSF3, CFIm levels are strongly reduced, which exposes the pPASs and leads to shorter 3’UTRs. Conversely, during cellular differentiation, 3’UTRs are massively extended, while the levels of SRSF7 and FIP1 strongly decline. Altogether, our data suggest that SRSF7 acts as a sequence-specific enhancer of pPASs, while SRSF3 inhibits pPAS usage by controlling CFIm levels. Our data shed light on a long-standing puzzle of how one factor (CFIm) can inhibit and enhance PAS usage.
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Project description:Label the cells overexpressed Flag tagged YTHDC1, SRSF1, SRSF3, SRSF7, SRSF9 and SRSF10 with 4-SU, the RNA bound by YTHDC1 and SRSF proteins can be got by Flag IP followed by RNA isolation by using the TRIzol (Invitrogen) reagent by following the company manual.the RNA was then used for library preparation using a TruSeq⢠RNA Sample Prep Kit v2 (Illumina, San Diego, CA, USA) according to the manufacturerâs protocol.The libraries were sequenced using HiSeq2000 (Illumina) in single-read mode, creating reads with a length of 101 bp. Sequencing chemistry v2 (Illumina) was used and samples were multiplexed in two samples per lane. Discovery of the binding motif of YTHDC1, SRSF1, SRSF3, SRSF7, SRSF9 or SRSF10 in overexpressed Human HeLa cells
2016-02-17 | E-GEOD-71096 | biostudies-arrayexpress
Project description:Alternative polyadenylation (APA) refers to the regulated selection of polyadenylation sites (PASs) in transcripts, which determines the length of their 3’ untranslated regions (3’UTRs). APA regulates stage- and tissue-specific gene expression by affecting the stability, subcellular localization and translation rate of transcripts. We have recently shown that SRSF3 and SRSF7, two closely related SR proteins, connect APA with mRNA export. The mechanism underlying APA regulation by SRSF3 and SRSF7 remained, however, unknown. Here, we combined iCLIP, RNA-Seq and 3’-end sequencing to find that both proteins bind upstream of proximal PASs (pPASs), yet they exert opposite effects on 3’UTR length. We show that SRSF7 enhances pPAS usage in a concentration-dependent but splicing-independent manner by recruiting the cleavage factor FIP1, thereby generating short 3’UTRs. Protein domains unique to SRSF7, which are absent from SRSF3, and hypo-phosphorylation contribute to FIP1 recruitment. In contrast, SRSF3 promotes distal PAS (dPAS) usage and hence long 3’UTRs by maintaining high levels of cleavage factor Im (CFIm) via alternative splicing. Upon reduced expression of SRSF3, CFIm levels strongly decrease and 3’UTRs are globally shortened. In SRSF3-regulated transcripts, CFIm and FIP1 bind upstream of dPASs and promote their usage. Surprisingly, both factors are also recruited to pPASs under conditions where their usage is blocked, suggesting the formation of inactive cleavage complexes. Thus, we identify SRSF3 as a novel regulator of CFIm activity, provide evidence that CFIm inhibits pPAS usage and show that small differences in the domain architecture of SR proteins confer opposite effects on PAS selection.
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