Metastasis-repressive CircRNA MASCOT Regulates Distribution of the Splicing Factor hnRNP M
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ABSTRACT:
PROVIDER: PRJNA882061 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21627300_1.fastq.gz | Fastqsanger.gz | |||
| SRR21627300_2.fastq.gz | Fastqsanger.gz | |||
| SRR21627289_1.fastq.gz | Fastqsanger.gz | |||
| SRR21627289_2.fastq.gz | Fastqsanger.gz | |||
| SRR21627290_1.fastq.gz | Fastqsanger.gz |
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Project description:Alternative splicing (AS) diversifies the transcriptome complexity and is usually hijacked by cancer cells. Here, we identified heterogeneous nuclear ribonucleoprotein M (hnRNP M) as an indispensable contributor to EMT-related AS reprogramming, whose sub-nuclear distribution of hnRNP M is altered in metastatic tumors. Upon TGFβ stimulation, hnRNP M trends to disassociate with a circRNA called MASCOT (hnRNP M-ASsociated Circular RNA Of TGFβ) that demonstrated an impressive inhibitory effect on EMT process and tumor metastasis. Mechanistically, the anti-metastatic effect of MASCOT is attributed to not only its competition with U2 RNA splicing factors to recruit hnRNP M in the nucleoplasm, but also the anchorage of hnRNP M with nucleolin into the nucleolus to cause a temporospatial separation of hnRNP M from spliceosome. Moreover, the correlation between MASCOT expression and hnRNP M sub-nuclear localization was validated in clinical specimens. Our study deciphers the regulatory codes controlling AS networks and highlights MASCOT as a promising therapeutic to treat metastasis.
2022-09-10 | GSE165576 | GEO
Project description:Alternative splicing (AS) diversifies the transcriptome complexity and is usually hijacked by cancer cells. Here, we identified heterogeneous nuclear ribonucleoprotein M (hnRNP M) as an indispensable contributor to EMT-related AS reprogramming, whose sub-nuclear distribution of hnRNP M is altered in metastatic tumors. Upon TGFβ stimulation, hnRNP M trends to disassociate with a circRNA called MASCOT (hnRNP M-ASsociated Circular RNA Of TGFβ) that demonstrated an impressive inhibitory effect on EMT process and tumor metastasis. Mechanistically, the anti-metastatic effect of MASCOT is attributed to not only its competition with U2 RNA splicing factors to recruit hnRNP M in the nucleoplasm, but also the anchorage of hnRNP M with nucleolin into the nucleolus to cause a temporospatial separation of hnRNP M from spliceosome. Moreover, the correlation between MASCOT expression and hnRNP M sub-nuclear localization was validated in clinical specimens. Our study deciphers the regulatory codes controlling AS networks and highlights MASCOT as a promising therapeutic to treat metastasis.
2022-09-20 | GSE213677 | GEO
Project description:Metastasis-repressive CircRNA MASCOT Regulates Distribution of the Splicing Factor hnRNP M
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Project description:Alternative splicing (AS) is a key regulatory mechanism that expands transcriptomic diversity and is frequently hijacked by cancer cells to drive epithelial-mesenchymal transition (EMT), thereby promoting invasion and therapy resistance. However, therapeutic strategies to reprogram pathological AS networks remain limited. Here, we identified a circular RNA, MASCOT (hnRNP M-ASsociated Circular RNA Of TGFβ), that functions as an endogenous aptamer targeting the splicing factor hnRNP M, a central regulator of EMT-related AS reprogramming. As an endogenous repressor of hnRNP M, MASCOT maintains the epithelial status of cancer cells and suppresses tumor metastasis. Conversely, its downregulation by TGFβ releases hnRNP M to initiate EMT-associated splicing changes. Restoring MASCOT expression significantly reduces metastatic burden in mouse models. Mechanistically, MASCOT scaffolds hnRNP M to nucleolin within the nucleolus, spatially sequestering hnRNP M away from the spliceosome. Our findings reveal a novel regulatory circuit that controls EMT-linked splicing and identify MASCOT as a promising RNA-based therapeutic candidate against metastatic progression.
2026-08-04 | GSE335525 | GEO
Project description:Alternative splicing (AS) is a key regulatory mechanism that expands transcriptomic diversity and is frequently hijacked by cancer cells to drive epithelial-mesenchymal transition (EMT), thereby promoting invasion and therapy resistance. However, therapeutic strategies to reprogram pathological AS networks remain limited. Here, we identified a circular RNA, MASCOT (hnRNP M-ASsociated Circular RNA Of TGFβ), that functions as an endogenous aptamer targeting the splicing factor hnRNP M, a central regulator of EMT-related AS reprogramming. As an endogenous repressor of hnRNP M, MASCOT maintains the epithelial status of cancer cells and suppresses tumor metastasis. Conversely, its downregulation by TGFβ releases hnRNP M to initiate EMT-associated splicing changes. Restoring MASCOT expression significantly reduces metastatic burden in mouse models. Mechanistically, MASCOT scaffolds hnRNP M to nucleolin within the nucleolus, spatially sequestering hnRNP M away from the spliceosome. Our findings reveal a novel regulatory circuit that controls EMT-linked splicing and identify MASCOT as a promising RNA-based therapeutic candidate against metastatic progression.
2026-08-04 | GSE336555 | GEO
Project description:Understanding how RNA binding proteins control the splicing code is fundamental to human biology and disease. Here we present a comprehensive study to elucidate how heterogeneous nuclear ribonucleoparticle (hnRNP) proteins, among the most abundant RNA binding proteins, coordinate to regulate alternative pre-mRNA splicing (AS) in human cells. Using splicing-sensitive microarrays, cross-linking and immunoprecipitation coupled with high-throughput sequencing, and cDNA sequencing, we find that more than half of all AS events are regulated by multiple hnRNP proteins, and that some combinations of hnRNP proteins exhibit significant synergy, whereas others act antagonistically. Our analyses reveal position-dependent RNA splicing maps, in vivo consensus binding sites, a surprising level of cross- and auto-regulation among hnRNP proteins, and the coordinated regulation by hnRNP proteins of dozens of other RNA binding proteins and genes associated with cancer. Our findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells. In triplicate, polyA-selected RNA was extracted from control, hnRNP A1, hnRNP A2/B1, hnRNP H1, hnRNP F, hnRNP M, and hnRNP U siRNA treated human 293T cells, and hybridized to custom splice-junction arrays
2012-02-20 | E-GEOD-34992 | biostudies-arrayexpress
Project description:Back-splicing is a non-canonical splicing event that drives the biogenesis of circular RNAs (circRNAs). Although the molecular mechanisms underlying circRNA biogenesis have been partially elucidated, how this process is globally regulated in tumors that show a general repression of circRNAs, such as medulloblastoma (MB), has not been fully investigated. Herein, we uncover a hnRNP C-dependent mechanism that represses a broad repertoire of circRNAs in Group 3 MB. HnRNP C binds Alu elements and prevents non-colinear splicing, thus repressing circularization of pre-mRNA transcripts. Expression of hnRNP C modulates the balance between linear and circular splicing and guarantees efficient expression of genes that sustain the oncogenic phenotype of Group 3 MB cells. Remarkably, in the absence of hnRNP C, the introns flanking the circularizing exons generated cytoplasmic dsRNAs through base-pairing of inverted Alu elements and, consequently, triggered an interferon-induced antiviral defense mechanism. These findings unveil the role of hnRNP C as guardian of transcriptome integrity by repressing circRNA biogenesis and suggest that targeting hnRNP C in Group 3 MB may be used to trigger an inflammatory immune response, thereby boosting cancer surveillance.
2026-03-20 | GSE304204 | GEO
Project description:Understanding how RNA binding proteins control the splicing code is fundamental to human biology and disease. Here we present a comprehensive study to elucidate how heterogeneous nuclear ribonucleoparticle (hnRNP) proteins, among the most abundant RNA binding proteins, coordinate to regulate alternative pre-mRNA splicing (AS) in human cells. Using splicing-sensitive microarrays, cross-linking and immunoprecipitation coupled with high-throughput sequencing, and cDNA sequencing, we find that more than half of all AS events are regulated by multiple hnRNP proteins, and that some combinations of hnRNP proteins exhibit significant synergy, whereas others act antagonistically. Our analyses reveal position-dependent RNA splicing maps, in vivo consensus binding sites, a surprising level of cross- and auto-regulation among hnRNP proteins, and the coordinated regulation by hnRNP proteins of dozens of other RNA binding proteins and genes associated with cancer. Our findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells.
2012-02-20 | GSE34992 | GEO
Project description:HnRNP K is a heterogeneous nuclear ribonucleoprotein and has been identified as an oncogene in most solid tumors via regulating gene expression or alternative splicing of genes by binding both DNA and pre-mRNA. However, how hnRNP K affects tumorigenesis and regulates the gene expression in cervical cancer (CESC) remains to be elucidated. In these data, higher expression of hnRNP K was observed in CESC and was negatively correlated with the patient survival time. We then overexpressed hnRNP K (hnRNP K-OE) and found that its overexpression promoted cell proliferation in HeLa cells (P = 0.0052). Next, global transcriptome sequencing (RNA-seq) experiments were conducted to explore gene expression and alternative splicing profiles regulated by hnRNP K. It is shown that upregulated genes by hnRNP K-OE were associated with inflammatory response and an apoptotic process of neuron cells, which involves in cancer. In addition, the alternative splicing of those genes regulated by hnRNP K-OE was associated with transcriptional regulation. Analysis of the binding features of dysregulated transcription factors (TFs) in the promoter region of the inflammatory response genes regulated by hnRNP K revealed that hnRNP K may modulate the expression level of genes related to inflammatory response by influencing the alternative splicing of TFs. Among these hnRNP K-TFs-inflammatory gene regulatory networks, quantitative reverse transcription polymerase chain reaction (RT-qPCR) experiments and gene silencing were conducted to verify the hnRNP K-IRF1-CCL5 axis. In conclusion, the hnRNP K-TFs-inflammatory gene regulatory axis provides a novel molecular mechanism for hnRNP K in promoting CESC and offers a new therapeutic target.
2023-02-19 | GSE148385 | GEO
Project description:Understanding how RNA binding proteins control the splicing code is fundamental to human biology and disease. Here we present a comprehensive study to elucidate how heterogeneous nuclear ribonucleoparticle (hnRNP) proteins, among the most abundant RNA binding proteins, coordinate to regulate alternative pre-mRNA splicing (AS) in human cells. Using splicing-sensitive microarrays, cross-linking and immunoprecipitation coupled with high-throughput sequencing, and cDNA sequencing, we find that more than half of all AS events are regulated by multiple hnRNP proteins, and that some combinations of hnRNP proteins exhibit significant synergy, whereas others act antagonistically. Our analyses reveal position-dependent RNA splicing maps, in vivo consensus binding sites, a surprising level of cross- and auto-regulation among hnRNP proteins, and the coordinated regulation by hnRNP proteins of dozens of other RNA binding proteins and genes associated with cancer. Our findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells. RNAseq for control, hnRNP A1, hnRNP A2/B1, hnRNP H1, hnRNP F, hnRNP M, and hnRNP U siRNA treated human 293T cells
2012-02-20 | E-GEOD-34995 | biostudies-arrayexpress