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LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity [RNA-seq]

ABSTRACT: LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity [RNA-seq]

PROVIDER: PRJNA942955 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23782851_1.fastq.gz	Fastqsanger.gz
	SRR23782851_2.fastq.gz	Fastqsanger.gz
	SRR23782852_1.fastq.gz	Fastqsanger.gz
	SRR23782852_2.fastq.gz	Fastqsanger.gz
	SRR23782853_1.fastq.gz	Fastqsanger.gz

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LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity [iCLIP]

Project description:RNA splicing plays a critical role in post-transcriptional gene regulation. Exponential expansion of intron length poses a challenge for accurate splicing. Little is known about how cells prevent inadvertent and often deleterious expression of intronic elements due to cryptic splicing. In this study, we identify hnRNPM as an essential RNA binding protein that suppresses cryptic splicing through binding to deep introns, preserving transcriptome integrity. Long interspersed nuclear elements (LINEs) harbor large amounts of pseudo splice sites in introns. hnRNPM preferentially binds at intronic LINEs and represses LINE-containing pseudo splice site usage for cryptic splicing. Remarkably, a subgroup of the cryptic exons can form long dsRNAs through base-pairing of inverted Alu transposable elements scattered in between LINEs and trigger interferon immune response, a well-known antiviral defense mechanism. Notably, these interferon-associated pathways are found to be upregulated in hnRNPM-deficient tumors, which also exhibit elevated immune cell infiltration. These findings unveil hnRNPM as a guardian of transcriptome integrity. Targeting hnRNPM in tumors may be used to trigger an inflammatory immune response thereby boosting cancer surveillance.

2024-05-29 | GSE227048 | GEO

LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity

Project description:LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity

| PRJNA942957 | ENA

LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity [RNA-seq]

2024-05-29 | GSE227047 | GEO

LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity [iCLIP]

Project description:LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity [iCLIP]

| PRJNA942961 | ENA

LINE-associated cryptic splicing induces dsRNA-mediated interferon response and tumor immunity

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-05-29 | GSE227050 | GEO

A neurotoxic cryptic peptide arising from TDP-43-dependent cryptic splicing of PKN1

Project description:Transactive response DNA-binding protein 43 (TDP-43) is a key factor in maintaining the fidelity of neuronal RNA splicing, and its dysfunction is observed in amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) with TDP-43 pathology. Although loss of TDP-43 can activate multiple cryptic splicing events, whether specific cryptic exons generate stable and toxic peptides remains unclear. Here, we identify a TDP-43–dependent cryptic splicing event (PKN1-5a1) in the serine/threonine kinase gene PKN1: in transcriptomes of ALS patient brains it is markedly activated, inserting a 127-bp unannotated exon and introducing multiple premature termination codons. We further show that this aberrant transcript can partially escape nonsense-mediated mRNA decay (NMD) and is translated into a truncated peptide, N207; in AD brains with TDP-43 pathology, N207 is also detected by a specific antibody. Functional studies indicate that N207 overexpression impairs cognitive behaviors and weakens synaptic plasticity. These results indicate that cryptic splicing resulting from dysregulated TDP-43 not only causes loss of protein function but can also generate truncated toxic peptides that evade NMD, providing a new molecular-level explanation for the pathogenesis of TDP-43–related proteinopathies.

2025-10-11 | PXD069368 |

Function of HNRNPC in breast cancer cells by controlling the dsRNA-induced interferon response

Project description:Elevated expression of RNA binding protein HNRNPC has been reported in cancer cells, while the essentialness and functions of HNRNPC in tumors were not clear. We showed that repression of HNRNPC in the breast cancer cells MCF7 and T47D inhibited cell proliferation and tumor growth. Our computational inference of the key pathways and extensive experimental investigations revealed that the cascade of interferon responses mediated by RIG-I was responsible for such tumor-inhibitory effect. Interestingly, repression of HNRNPC resulted in accumulation of endogenous double-stranded RNA (dsRNA), the binding ligand of RIG-I. These up-regulated dsRNA species were highly enriched by Alu sequences and mostly originated from pre-mRNA introns that harbor the known HNRNPC binding sites. Such source of dsRNA is different than the recently well-characterized endogenous retroviruses that encode dsRNA. In summary, essentialness of HNRNPC in the breast cancer cells was attributed to its function in controlling the endogenous dsRNA and the down-stream interferon response. This is a novel extension from the previous understandings about HNRNPC in binding with introns and regulating RNA splicing.

2018-08-23 | GSE100451 | GEO

Pathogenic Proteotoxicity of Cryptic Splicing is Alleviated by Ubiquitination and ER-Phagy

Project description:RNA splicing and protein degradation systems allow functional adaptation of the proteome in response to changing cellular contexts. However, the regulatory mechanisms connecting these processes remain poorly understood. Here, we show that impaired spliceosome assembly caused by USP39 deficiency leads to a pathogenic splicing profile characterized by the use of cryptic 5′ splice sites. Importantly, disruptive cryptic variants evade mRNA surveillance pathways and are translated into misfolded proteins. These spurious isoforms disrupt proteostasis causing proteotoxic aggregates, ER stress and CHOP-mediated cell death. In response to impaired splicing, eukaryotic cells enhance ubiquitination and ER-phagy to alleviate the pathogenic translation of proteotoxic exons. Our findings show how cryptic splicing-inducedproteotoxicity can be mitigated, and provide insight into the molecular pathogenesis of spliceosome-associated diseases, such as retinitis pigmentosa.

2024-09-25 | PXD051146 | Pride

Pathogenic Proteotoxicity of Cryptic Splicing is Alleviated by Ubiquitination and ER-Phagy

Project description:RNA splicing and protein degradation systems allow the functional adaptation of the proteome in response to changing cellular contexts. However, the regulatory mechanisms connecting these processes remain poorly understood. Here, we show that impaired spliceosome assembly caused by USP39 deficiency leads to a pathogenic splicing profile characterized by the use of cryptic 5′ splice sites. Importantly, disruptive cryptic variants evade mRNA surveillance pathways and are translated into misfolded proteins. These spurious isoforms disrupt proteostasis causing cytosolic protein aggregates and ER stress. Proteotoxic exons activate unfolded protein response, causing CHOP-mediated cell death. In response to impaired splicing, eukaryotic cells enhance ubiquitination and ER-phagy to alleviate the pathogenic accumulation of proteotoxic isoforms. Our findings show how cryptic splicing-induced proteotoxicity can be mitigated, and provide insight into the molecular pathogenesis of spliceosome-associated diseases such as retinitis pigmentosa.

2024-09-25 | PXD050806 | Pride

MATR3 pathogenic variants differentially impair its cryptic splicing repression function

Project description:To investigate the role of MATR3 in splicing regulation, we performed RNA sequencing on HeLa cells treated with either control siRNA or MATR3 siRNA and then conducted alternative and cryptic splicing analysis

2024-01-10 | GSE205343 | GEO

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