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.
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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: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.
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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.
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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:RAD51 is a highly conserved DNA repair protein and is indispensable for the execution of homologous recombination, thereby participating in maintaining genomic stability. Since constitutive Rad51 knockout mice exhibit embryonic lethality, the physiological functions of RAD51, and the consequences of lacking it, are largely unknown. We herein demonstrated a critical role of RAD51 in postnatal liver development and regeneration. RAD51 is highly expressed during liver development and during regeneration following hepatectomy and hepatic injury, and is also elevated in liver-related diseases. We generated hepatocyte-specific Rad51 deletion mouse model (Rad51-CKO) to evaluate the function of RAD51 in liver development and regeneration.RAD51 deletion in postnatal hepatocytes results in aborted mitosis, global polyploidization, oxidative stress and cellular senescence. Remarkable liver fibrosis occurs as early as in 3-month-old Rad51fl/fl; Alb-Cre+/+ mice.The senescence-associated secretory phenotype in the livers of Rad51-CKO mice creates a niche that favors the activation and propagation of hepatic progenitor cells (HPCs) in which Rad51 is spared due to lack of Alb-Cre expression. The Rad51 functional HPCs and immature hepatocytes can thus proliferate vigorously, acquire increased malignancy, and eventually give rise to HCC. Our results thus demonstrate a novel function of RAD51 in liver development, homeostasis and tumorigenesis. The RAD51-CKO mice represent a unique genetic model for premature liver senescence, fibrosis, impaired regeneration and hepatocellular carcinogenesis.
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Project description:RAD51 is a highly conserved DNA repair protein and is indispensable for the execution of homologous recombination, thereby participating in maintaining genomic stability. Since constitutive Rad51 knockout mice exhibit embryonic lethality, the physiological functions of RAD51, and the consequences of lacking it, are largely unknown. We herein demonstrated a critical role of RAD51 in postnatal liver development and regeneration. RAD51 is highly expressed during liver development and during regeneration following hepatectomy and hepatic injury, and is also elevated in liver-related diseases. We generated hepatocyte-specific Rad51 deletion mouse model (Rad51-CKO) to evaluate the function of RAD51 in liver development and regeneration.RAD51 deletion in postnatal hepatocytes results in aborted mitosis, global polyploidization, oxidative stress and cellular senescence. Remarkable liver fibrosis occurs as early as in 3-month-old Rad51fl/fl; Alb-Cre+/+ mice.The senescence-associated secretory phenotype in the livers of Rad51-CKO mice creates a niche that favors the activation and propagation of hepatic progenitor cells (HPCs) in which Rad51 is spared due to lack of Alb-Cre expression. The Rad51 functional HPCs and immature hepatocytes can thus proliferate vigorously, acquire increased malignancy, and eventually give rise to HCC. Our results thus demonstrate a novel function of RAD51 in liver development, homeostasis and tumorigenesis. The RAD51-CKO mice represent a unique genetic model for premature liver senescence, fibrosis, impaired regeneration and hepatocellular carcinogenesis.
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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
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Project description:UBE3A encodes a E3 ubiquitin ligase whose loss from the maternal allele causes the neurodevelopmental disorder Angelman syndrome. Previous studies of UBE3A function have not examined full Ube3a deletion in mouse, the complexity of imprinted gene networks in brain, nor the molecular basis of systems-level cognitive dysfunctions in Angelman syndrome. We therefore utilized a systems biology approach to elucidate how UBE3A loss impacts the early postnatal brain in a novel CRISPR/Cas9 engineered rat Angelman model of a complete Ube3a deletion. Strand-specific transcriptome analysis of offspring from maternally or paternally inherited Ube3a deletions revealed the expected parental expression patterns of Ube3a sense and antisense transcripts by postnatal day 2 (P2) in hypothalamus and day 9 (P9) in cortex, compared to wild-type littermates. The dependency of genome-wide effects on parent-of-origin, Ube3a genotype, and time (P2, P9) was investigated through transcriptome (RNA-seq of cortex and hypothalamus) and methylome (whole genome bisulfite sequencing of hypothalamus). Weighted gene co-expression and co-methylation network analyses identified co-regulated networks in maternally inherited Ube3a deletion offspring enriched in postnatal developmental processes including Wnt signaling, synaptic regulation, neuronal and glial functions, epigenetic regulation, ubiquitin, circadian entrainment, and splicing. Furthermore, we showed that loss of the paternal Ube3a antisense transcript resulted in both unique and overlapping dysregulated gene pathways with maternal loss, predominantly at the level of differential methylation. Together, these results provide a holistic examination of the molecular impacts of UBE3A loss in brain, supporting the existence of interactive epigenetic networks between maternal and paternal transcripts at the Ube3a locus.
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