YTHDC1 affects the ubiquitination level of RAD51 by negatively regulating UBE3A expression and inhibits colorectal cancer cells apoptosis
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ABSTRACT:
PROVIDER: PRJNA1030288 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26448909_1.fastq.gz | Fastqsanger.gz | |||
| SRR26448909_2.fastq.gz | Fastqsanger.gz | |||
| SRR26448910_1.fastq.gz | Fastqsanger.gz | |||
| SRR26448910_2.fastq.gz | Fastqsanger.gz | |||
| SRR26448911_1.fastq.gz | Fastqsanger.gz |
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Project description:Understanding the role of YTHDC1 in colorectal cancer development and DNA damage repair is crucial for advancing treatment strategies. In our study, we found that YTHDC1 is expressed at significantly higher levels in high-malignancy tissues compared to low-malignancy tissues. Silencing YTHDC1 effectively inhibits the proliferation of colorectal cancer cell lines and significantly increases cell apoptosis. We identified RAD51 as a key downstream target of YTHDC1. Knockdown of YTHDC1 reduced RAD51 protein levels, while silencing RAD51 also inhibited cancer cell proliferation. Interestingly, RNA sequencing indicated that YTHDC1 deletion did not affect RAD51 transcription but increased its ubiquitination through WB experiment. Our analysis revealed that reducing YTHDC1 raised E3 ligase UBE3A levels, which is involved in RAD51 ubiquitination and ubiquitination experiments confirmed that RAD51 is one of the ubiquitination substrates of UBE3A. Co-immunoprecipitation experiments confirmed interactions among YTHDC1, UBE3A, and RAD51, suggesting they form a complex that regulates homologous repair processes. Our study provides new insights into how YTHDC1 modulates RAD51 ubiquitin levels through post-translational modifications, offering valuable information for developing effective colorectal cancer therapies.
2024-12-06 | GSE245860 | GEO
Project description:YTHDC1, a key protein in the m6A-related regulatory network within cells, is involved in multiple cellular processes such as chromatin-related regulation, RNA splicing, and nuclear export. Understanding its role in colorectal cancer (CRC) development and DNA damage repair is critical for the advancement of treatment strategies. Our study found that YTHDC1 was highly expressed in high-malignancy CRC tissues compared with low-malignancy ones. Upon silencing YTHDC1, we observed a pronounced suppression of the proliferation of CRC cell lines, accompanied by a substantial increase in cell apoptosis. Furthermore, we identified RAD51 as a crucial downstream target of YTHDC1. Knocking down YTHDC1 led to a notable decrease in RAD51 protein levels, and silencing RAD51 also inhibited cancer cell proliferation. Interestingly, RNA-sequencing data indicated that the YTHDC1 deletion did not affect RAD51 transcription. However, Western blot revealed that this deletion increased the ubiquitination of RAD51, likely due to the upregulated E3 ligase UBE3A. Ubiquitination experiments subsequently confirmed that RAD51 is indeed one of the substrates of UBE3A. In summary, our study provides novel insights into how YTHDC1 modulates the expression of RAD51 through post-translational modifications. These findings offer valuable information that may potentially contribute to the development of more effective therapeutic strategies for CRC.
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Project description:The autism spectrum disorders (ASD) are a collection of disorders with heterogeneous etiology, exhibiting common traits including impaired social interactions and communications, repetitive behaviors. 15q11-q13 copy number variations (CNV) were found in 1-3% of ASD cases; of which the detailed mechanism of the major contributor UBE3A gene acted still remained elusive. Here we identified a key enzyme in RA synthesis, negatively regulated in ubiquitination-dependent mode promoted by UBE3A. Our data provide evidences linking UBE3A hyperactivity with ASD phenotypes, with implications for understanding ASD etiology and providing potential interventions in ASD clinical therapy.
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Project description:X-linked inhibitor of apoptosis protein (XIAP), a member of the IAP family, is overexpressed in a variety of tumors and plays an important role in tumor progression. Increasing evidence suggests that XIAP promotes metastasis of bladder cancer but the underlying mechanism is not very clear. The RNA N6-methyladenosine (m6A) reader YTHDC1 regulates RNA splicing, nuclear transport, and mRNA stability and is a potential tumor target; however, its ubiquitin E3 ligase has not been described. In this study, screening of proteins that specifically interact with XIAP identified YTHDC1 to be its degradation substrate. Ectopic overexpression of XIAP promoted degradation of YTHDC1, and knockout of XIAP upregulated YTHDC1, which inhibited metastasis of bladder cancer. Furthermore, YTHDC1 reduced expression of matrix metalloproteinase-2 (MMP-2) by destabilizing its mRNA. These experiments revealed that XIAP promotes ubiquitination of YTHDC1, positively regulating expression of MMP-2 and promoting metastasis of bladder cancer. Collectively, these findings demonstrate that XIAP is a critical regulator of YTHDC1 and pinpoint the XIAP/YTHDC1/MMP-2 axis as a promising target for the treatment of bladder cancer.
2025-05-07 | PXD055868 | Pride
Project description:Angelman syndrome is a neurodevelopmental disorder caused by (epi)genetic lesions of maternal UBE3A. Research has focused largely on the role of UBE3A in neurons due to its imprinting in that cell type. Yet, evidence suggests there may be broader neurodevelopmental impacts of UBE3A dysregulation. Human cerebral organoids can investigate these understudied aspects of UBE3A as they recapitulate diverse cell types of the developing human brain. We performed single-cell RNA-sequencing on organoids to reveal the effects of UBE3A disruption on cell type-specific transcriptomic alterations and compositions. In the absence of UBE3A, progenitor proliferation and structures were disrupted while organoid composition shifted away from proliferative cell types. We observed impacts on non-neuronal cells including choroid plexus enrichment. Furthermore, EMX1+ cortical progenitors were negatively impacted, disrupting corticogenesis, and potentially delaying neuron maturation. This work reveals novel impacts of UBE3A on understudied cell types and related neurodevelopmental processes and elucidates potential new therapeutic targets.
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Project description:This strand-specific array is performed to characterize expression features of Ube3a-ATS, including its imprinting status, its exon-intron structure, its transcriptional initiation and termination site as well as its polyadenylation status. The array contains reverse-complementary probes detecting transcripts from both strands and therefore we are able to pick up signal from both Ube3a sense and antisense. By comparing wild-type with various mutants, and total RNA with polyA RNA, we concluded that Ube3a-ATS is a paternally imprinted gene covering the whole gene body of Ube3a in the antisense orientation. It does not have an obvious exon-intron structure. Its transcription initiates at Snrpn major promoter and terminates ~40kb upstream of Ube3a transcriptional start site. Total RNA from Snrpn-Ube3a maternal deletion mutant (del s-u/+), its wild-type littermate, paternal deletion mutant and its wildtype littermate were analyzed. Mutant mice with S-U maternal deletion and Snrpn promoter paternal deleiton which leads to depletion of Ube3a-ATS (del s-u/0.9 and del s-u/4.8) were also analyzed. polyA RNA was purified from the sample 2 and sample 4. All eight samples were hybridized to the custom 8X60k Agilent CGH array.
2012-05-02 | E-GEOD-29254 | biostudies-arrayexpress
Project description:This strand-specific array is performed to characterize expression features of Ube3a-ATS, including its imprinting status, its exon-intron structure, its transcriptional initiation and termination site as well as its polyadenylation status. The array contains reverse-complementary probes detecting transcripts from both strands and therefore we are able to pick up signal from both Ube3a sense and antisense. By comparing wild-type with various mutants, and total RNA with polyA RNA, we concluded that Ube3a-ATS is a paternally imprinted gene covering the whole gene body of Ube3a in the antisense orientation. It does not have an obvious exon-intron structure. Its transcription initiates at Snrpn major promoter and terminates ~40kb upstream of Ube3a transcriptional start site.
2012-05-03 | GSE29254 | GEO
Project description:Ubiquitin-protein ligase E3A (UBE3A) has dual functions as a E3 ubiquitin-protein ligase and coactivator of nuclear hormone receptors. Mutations or deletions of the maternally inherited UBE3A gene cause Angelman syndrome. Here, we performed transcriptome profiling in the hippocampus of Ube3am+/p+ and Ube3am-/p+ mice, and determined that the expression of the retinoic acid (RA) signalling pathway was downregulated in Ube3a-deficient mice compared to WT mice. Furthermore, we demonstrated that UBE3A directly interacts with RARα and may function as a coactivator of the nuclear receptor RARα to participate in the regulation of gene expression. Loss of UBE3A expression caused the downregulation of the expression of RA-related genes, including Erbb4, Dpysl3, Calb1, Pten and Arhgap5 in Ube3am-/p+ mice brain tissues. This work revealed a new role for UBE3A in regulating retinoic acid (RA) signalling downstream genes and hopefully to shed light on the potential drug target of AS.
2021-03-15 | GSE168889 | GEO
Project description:Here, we investigated the neurodevelopmental impact of Ube3a gene overdosage using bacterial artificial chromosome-based transgenic mouse models (Ube3aOE) that recapitulate the increases in Ube3a copy number most often observed in Dup15q.Here, we investigated the neurodevelopmental impact of Ube3a gene overdosage using bacterial artificial chromosome-based transgenic mouse models (Ube3aOE) that recapitulate the increases in Ube3a copy number most often observed in Dup15q. Hereto we performed gene expression profiling analysis using data obtained from RNA-seq of cortical and hippocampal tissue from wildtype and Ube3aOE mice
2022-08-04 | GSE205128 | GEO
Project description:Mutations in the E3 ubiquitin ligase UBE3A that cause enzymatic gain-of-function result in heterogeneous disease phenotypes in humans which differ from classic Angelman syndrome. We describe two affected siblings who possess an inherited UBE3AL734S variant that causes a strong gain in UBE3A activity. Unlike previously described cases, these individuals exhibited borderline microcephaly, suggesting the extent of UBE3A gain-of-function can produce neomorphic phenotypes. Here, we characterize a mouse model harboring a strong gain of function variant (Ube3aQ606E) which elevates UBE3A activity 388% above wild type (WT) enzyme levels. We conduct extensive behavioral phenotyping to show that Ube3amQ606E mutants show motor deficits, hypoactivity, and reduced stereotypic behaviors. Brain weights and MRI analysis revealed global microcephaly with a postnatal onset. Proteomic analysis performed on neonatal cortex revealed perturbations in several key proteins and pathways linked to neurodevelopmental disease. Finally, we show that microcephaly is not caused by increased apoptotic cell death. Together, our results provide strong evidence that the type and severity of disease phenotypes depend on the causative UBE3A gain of function mutation and provide new insights into the phenotypic heterogeneity observed in individuals with UBE3A gain of function variants.
2025-05-07 | PXD055901 | Pride