Identification of pathological pathways centered on circRNA dysregulation initiated at a critical window of Alzheimer’s disease progression
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ABSTRACT:
PROVIDER: PRJNA992028 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25180256_1.fastq.gz | Fastqsanger.gz | |||
| SRR25180256_2.fastq.gz | Fastqsanger.gz | |||
| SRR25180257_1.fastq.gz | Fastqsanger.gz | |||
| SRR25180257_2.fastq.gz | Fastqsanger.gz | |||
| SRR25180258_1.fastq.gz | Fastqsanger.gz |
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Project description:Although circRNA abnormalities are found in Alzheimer’s disease (AD) postmortem brains, whether and how altered circRNA landscape lead to pathological gene network changes during AD progression remain undefined. Employing our recently published experimental and computational approaches, we found genome-wide dysregulated circRNA expression and disrupted functional cooperation of circRNAs in sponging microRNAs (miRNAs) and RNA-binding proteins (RBPs) during early pathogenic progression in a mouse AD model. In addition, we identified AD progression-associated mouse circRNAs that are conserved and affected in AD patients, which underlie malfunction of downstream microRNAs and RBPs in AD brains. An exemplar circRNA is circGigyf2, which progressively declines along with AD pathogenic severity. Furthermore, we identified AD pathological pathways centered on circGigyf2, including upstream RBPs that control circGigyf2 biogenesis and downstream miRNA-mRNA and RBP-mRNA axis regulated by circGigyf2, all affected in AD patients. Our discoveries provide strong evidence suggesting the contribution of circRNA abnormality in early AD pathogenesis.
2024-10-22 | GSE236683 | GEO
Project description:Identification of pathological pathways centered on circRNA dysregulation associated with irreversible progression of Alzheimer’s disease [5xFADHippocampus]
| PRJNA1138662 | ENA
Project description:Identification of pathological pathways centered on circRNA dysregulation associated with irreversible progression of Alzheimer’s disease [circGigyf2KD]
| PRJNA1138661 | ENA
Project description:Background Circular RNAs (circRNAs) are highly stable regulatory molecules, often accumulated in the mammalian brain and thought to serve as “memory molecules” that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in postmortem cortical regions of Alzheimer’s disease (AD) patients. However, whether and how circRNA dysregulation underlies AD progression remains unexplored. Methods Poly(A)-tailing/RNase R digestion was coupled with our recently published computational algorithm CARP to identify genome-wide dysregulation of circRNAs and their downstream pathways in the 5xFAD mouse cerebral cortex between 5- and 7-month of age, a critical window that marks the transition from reversible to irreversible pathogenic progression. Irreversibly dysregulated circRNAs and pathways in 5xFAD cortex were systematically compared with a large human AD cohort study. A top ranked circRNA conserved and commonly affected in AD patients and 5xFAD mice was depleted in cultured cells to confirm its causal roles in AD-relevant molecular and cellular changes. Results We discovered genome-wide circRNA alterations specifically in the 5xFAD cortex associated with AD progression and found numerous circRNAs also consistently affected in AD patient postmortem cortical areas. Among such circRNAs, circGigyf2 showed the highest net reduction starting from 7-month of age, which is highly conserved and negatively correlated with human AD severity. Mechanistically, we found multiple AD-affected splicing factors that are essential for circGigyf2 biogenesis. Functionally, we identified and experimentally validated the conserved roles of circGigyf2 in sponging AD-relevant miRNAs and AD-associated RNA binding proteins (RBPs) including the cleavage and polyadenylation factor 6 (CPSF6). CircGigyf2 downregulation in AD exert silencing activities of its sponged miRNAs and aberrantly enhanced the polyadenylation efficiency of many CPSF6 targets. These post-transcriptionally tuned mRNAs by circGigyf2 were enriched in apoptotic pathways. Furthermore, circGigyf2 depletion in a mouse immortalized neuronal cell line dysregulated circGigyf2-miRNA and circGigyf2-CPSF6 axes and potentiated neuronal responses to apoptotic insults, which strongly support the causative role of circGigyf2 deficiency in AD disease progression. Conclusions Together, our results unveiled pathological alterations of the brain circRNA landscape associated with irreversible disease stage in an AD mouse model and identified novel molecular mechanisms underlying dysregulation of conserved circRNA pathways that contribute to AD pathogenesis.
2024-10-22 | GSE272744 | GEO
Project description:Background Circular RNAs (circRNAs) are highly stable regulatory molecules, often accumulated in the mammalian brain and thought to serve as “memory molecules” that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in postmortem cortical regions of Alzheimer’s disease (AD) patients. However, whether and how circRNA dysregulation underlies AD progression remains unexplored. Methods Poly(A)-tailing/RNase R digestion was coupled with our recently published computational algorithm CARP to identify genome-wide dysregulation of circRNAs and their downstream pathways in the 5xFAD mouse cerebral cortex between 5- and 7-month of age, a critical window that marks the transition from reversible to irreversible pathogenic progression. Irreversibly dysregulated circRNAs and pathways in 5xFAD cortex were systematically compared with a large human AD cohort study. A top ranked circRNA conserved and commonly affected in AD patients and 5xFAD mice was depleted in cultured cells to confirm its causal roles in AD-relevant molecular and cellular changes. Results We discovered genome-wide circRNA alterations specifically in the 5xFAD cortex associated with AD progression and found numerous circRNAs also consistently affected in AD patient postmortem cortical areas. Among such circRNAs, circGigyf2 showed the highest net reduction starting from 7-month of age, which is highly conserved and negatively correlated with human AD severity. Mechanistically, we found multiple AD-affected splicing factors that are essential for circGigyf2 biogenesis. Functionally, we identified and experimentally validated the conserved roles of circGigyf2 in sponging AD-relevant miRNAs and AD-associated RNA binding proteins (RBPs) including the cleavage and polyadenylation factor 6 (CPSF6). CircGigyf2 downregulation in AD exert silencing activities of its sponged miRNAs and aberrantly enhanced the polyadenylation efficiency of many CPSF6 targets. These post-transcriptionally tuned mRNAs by circGigyf2 were enriched in apoptotic pathways. Furthermore, circGigyf2 depletion in a mouse immortalized neuronal cell line dysregulated circGigyf2-miRNA and circGigyf2-CPSF6 axes and potentiated neuronal responses to apoptotic insults, which strongly support the causative role of circGigyf2 deficiency in AD disease progression. Conclusions Together, our results unveiled pathological alterations of the brain circRNA landscape associated with irreversible disease stage in an AD mouse model and identified novel molecular mechanisms underlying dysregulation of conserved circRNA pathways that contribute to AD pathogenesis.
2024-10-22 | GSE272745 | GEO
Project description:Arraystar Human circRNA Microarray is designed for the global profiling of human circRNAs. In this study, we applied a circRNA microarray to screen the potential biomarker for HCC. 20 samples extracted from plasma samples including HCC group before operation, and after operation, CH group and control group. Each group contained five samples.
2021-03-02 | E-MTAB-8799 | biostudies-arrayexpress
Project description:Many studies have demonstrated the importance of circRNA in regulating gene expression through functioning as microRNA sponges. However, the roles of circRNA-protein interaction are not fully understood. Importantly, how circRNA-protein interaction contributes the progression of pancreatic ductal adenocarcinoma is largely unexplored. Therefore, RNA Pull down assay for investigating RNA-protein interaction was performed in PANC-1 cells.
2022-02-15 | PXD015048 | Pride
Project description:Circular RNAs (circRNAs), a noncoding RNA class originating from alternative splicing, are highly abundant in neural tissues and were shown to regulate gene expression e.g. by interacting with microRNAs and RNA-binding proteins. Neuroblastoma is an embryonal neoplasia, which arises from undifferentiated neural crest cells. Here, we aimed to explore, whether circRNAs influence the pathogenesis of high-risk neuroblastoma. We performed whole-transcriptome sequencing of 104 primary neuroblastoma samples of all risk-groups and identified 5,203 unique circRNAs involving 2,302 genes. Candidate circRNA expression did not correlate with host gene expression, indicating independent regulatory mechanisms. circRNAs were significantly downregulated in the MYCN-amplified high-risk tumors. These findings were independently reproduced in a tetracycline-inducible MYCN-overexpression system based on a non MYCN-amplified neuroblastoma cell line, suggesting that MYCN drives this global circRNA repression. We identified the RNA helicase DHX9 as a mediator of this global suppressive effect of MYCN on circRNAs. Comparing our RNA sequencing data with other cancers and controls revealed a circRNA subset specifically upregulated in neuroblastoma that included a circRNA derived from the ARID1A tumor suppressor gene. Specific circARID1A knockdown resulted in reduced proliferation, cell numbers and viability, prompted apoptosis and induced a differentiated phenotype. Neither knockdown, nor overexpression of circARID1A influenced ARID1A mRNA and protein levels significantly. To dissect the potential mode of function, we performed a pulldown assay with subsequent mass spectrometry. We identified the RNA-binding protein KHSRP as an interaction partner that participates in the mechanism of action of circARID1A. In summary, this study highlights an important role of circRNAs in neuroblastoma biology and may establish this RNA class as a future therapeutic target and biomarker.
2023-04-06 | PXD026053 | Pride
Project description:BackgroundCircular RNAs (circRNAs) are highly stable regulators, often accumulated in mammalian brains and thought to serve as "memory molecules" that govern the long process of aging. Mounting evidence demonstrated circRNA dysregulation in the brains of Alzheimer's disease (AD) patients. However, whether and how circRNA dysregulation underlies AD progression remains unexplored.MethodsWe combined Poly(A)-tailing/RNase R digestion experimental approach with CARP, our published computational framework using pseudo-reference alignment for more sensitive and accurate circRNA detection to identify genome-wide circRNA dysregulation and their downstream pathways in the 5xFAD mouse cerebral cortex between 5 and 7 months of age, a critical window marks the transition from reversible to irreversible pathogenic progression. Dysregulated circRNAs and pathways associated with disease progression in 5xFAD cortex were systematically compared with circRNAs affected in postmortem subcortical areas of a large human AD cohort. A top-ranked circRNA conserved and commonly affected in AD patients and 5xFAD mice was depleted in cultured cells to examine AD-relevant molecular and cellular changes.ResultsWe discovered genome-wide circRNA alterations specifically in 5xFAD cortex associated with AD progression, many of which are commonly dysregulated in the subcortical areas of AD patients. Among these circRNAs, circGigyf2 is highly conserved and showed the highest net reduction specifically in the 7-month 5xFAD cortex. CircGIGYF2 level in AD patients' cortices negatively correlated with dementia severity. Mechanistically, we found multiple AD-affected splicing factors that are essential for circGigyf2 biogenesis. Functionally, we identified and experimentally validated the conserved roles of circGigyf2 in sponging AD-relevant miRNAs and AD-associated RNA binding proteins (RBPs), including the cleavage and polyadenylation factor 6 (CPSF6). Moreover, circGigyf2 downregulation in AD promoted silencing activities of its sponged miRNAs and enhanced polyadenylation site processing efficiency of CPSF6 targets. Furthermore, circGigyf2 depletion in a mouse neuronal cell line dysregulated circGigyf2-miRNA and circGigyf2-CPSF6 axes and potentiated apoptotic responses upon insults, which strongly support the causative roles of circGigyf2 deficiency in AD neurodegeneration.ConclusionsTogether, our results unveiled brain circRNAs associated with irreversible disease progression in an AD mouse model that is also affected in AD patients and identified novel molecular mechanisms underlying the dysregulation of conserved circRNA pathways contributing to AD pathogenesis.
| S-EPMC11552301 | biostudies-literature
Project description:Diabetic retinopathy (DR) is one of the common chronic complications of diabetes. Circular RNA (circRNA) plays a vital role in the pathological process of diabetic retinopathy (DR), this study aims to explore the differences in circRNA expression profiles and functions between DR and non-DR patients.Serum from diabetes mellitus (DM) patients with DR (n=5) and without DR (n=5) were extracted for circRNA microarray analysis using Arraystar Human circRNA expression profile (v2.0). Another 5 DR and 5 non-DR patients were included for quantitative reverse transcription polymerase chain reaction (RT-qPCR) validation. Enriched signaling pathways were analyzed by GO and KEGG analysis. circRNA–miRNA networks were constructed by bioinformatics analysis.
2024-09-02 | GSE276127 | GEO