MiR-34 regulates JARID1A expresion (NB1691)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE49854 | GEO | 2014/01/01
SECONDARY ACCESSION(S): PRJNA215101
REPOSITORIES: GEO
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Project description:p53 inactivation occurs only rarely in neuroblastoma, although miR-34, a transcriptional target of p53, is often deleted in neuroblastoma, suggesting another way in which p53 signaling might be impaired. In this study we show that miR-34 directly targets and downregulates the Polycomb Repressive Complex 2 (PRC2) and its associated histone demethylase, JARID1A, in a p53-dependent manner, 8 samples were transfected with siRNA control or JMJD2B, MYCN, JARID1A into NB1691 cells.
2014-01-01 | E-GEOD-49854 | biostudies-arrayexpress
Project description:p53 inactivation occurs only rarely in neuroblastoma, although miR-34, a transcriptional target of p53, is often deleted in neuroblastoma, suggesting another way in which p53 signaling might be impaired. In this study we show that miR-34 directly targets and downregulates the Polycomb Repressive Complex 2 (PRC2) and its associated histone demethylase, JARID1A, in a p53-dependent manner,
2014-01-01 | GSE49845 | GEO
Project description:p53 inactivation occurs only rarely in neuroblastoma, although miR-34, a transcriptional target of p53, is often deleted in neuroblastoma, suggesting another way in which p53 signaling might be impaired. In this study we show that miR-34 directly targets and downregulates the Polycomb Repressive Complex 2 (PRC2) and its associated histone demethylase, JARID1A, in a p53-dependent manner, 4 samples were transfected with miRNA control or miR-34a, miR-34b, miR-34c into SK-N-BE2 cells.
2014-01-01 | E-GEOD-49845 | biostudies-arrayexpress
Project description:MiR-34a and miR-34b/c encoding genes represent direct targets of the p53 tumor suppressor. MiR-34a/b/c mediate tumor suppression by p53 via down-regulation of the expression of specific target mRNAs. Here, we characterized the miR-34 effectors using a CRISPR/Cas9-approach in HCT116 cells with or without 5-FU treatment.
2023-08-21 | GSE227230 | GEO
Project description:Histone H3K4 methylation has been linked to transcriptional activation. JARID1A (also known as RBP2 or KDM5A), a member of the JARID1 protein family, is an H3K4 demethylase, previously implicated in the regulation of transcription and differentiation. Here we show that JARID1A is physically and functionally associated with two histone deacetylase complexes. Immunoaffinity purification of JARID1A confirmed a previously described association with the SIN3B-containing HDAC complex, and revealed an association with the nucleosome remodeling and deacetylase (NuRD) complex. Sucrose density gradient and sequential immunoprecipitation analyses further confirmed the stable association of JARID1A with these two HDAC complexes. JARID1A depletion led to changes in the expression of hundreds of genes, two-thirds of which were also controlled by CHD4, the NuRD catalytic subunit. Gene ontology analysis confirmed that the genes commonly regulated by both JARID1A and CHD4 were categorized as developmentally regulated genes. ChIP analyses suggested that CHD4 controls chromatin association with JARID1A and modulates H3K4 levels at the promoter and coding regions of target genes. We further demonstrated that the C. elegans homologues of JARID1 and CHD4 function in the same pathway during vulva development. Taken together, these results suggest that JARID1A and the NuRD complex cooperatively function to control developmentally regulated genes.
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Project description:Diverse stresses and aging result in changes in expression levels of microRNAs, suggesting a role for these posttrancriptional regulators of gene expression in stress modulation and longevity. Earlier studies demonstrated a central role for the miR-34 family in promoting cell cycle arrest and cell death following stress in human cells. However, the biological significance of this response was unclear, because wildtype and miR-34 family knockouts tested under a variety of stress conditions showed no difference in cell survival in vitro or in vivo. Here, we addressed this question in C. elegans by analyzing the effect of different stress conditions on phenotype, transcriptome and mir-34 expression in animals deficient in or overexpressing mir-34. We showed that mir-34 upregulation is necessary for developmental arrest, correct morphogenesis, and adaptation to a lower metabolic state to protect animals against stress-related damages. Either deletion or overexpression of mir-34 lead to impaired stress response, which can largely be explained by perturbations in a DAF-16/FOXO target genes. We demonstrate that mir-34 expression is regulated by the insulin signaling pathway via a negative feedback loop between miR-34 and DAF-16/FOXO. We propose that mir-34 provides robustness to stress response programs by controlling noise in the DAF-16/FOXO-regulated gene network.
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Project description:Aging is a risk factor for neurodegenerative disease, but precise mechanisms that influence this relationship are still under investigation. Work in Drosophila melanogaster identified the microRNA miR-34 as a modifier of aging and neurodegeneration in the brain. MiR-34 mutants present aspects of early aging, including reduced lifespan, neurodegeneration, and a buildup of the repressive histone mark H3K27me3. To better understand how miR-34 regulated pathways contribute to age-associated phenotypes in the brain, here we transcriptionally profiled the miR-34 mutant brain. This identified that genes associated with translation are dysregulated in the miR-34 mutant. The brains of these animals show increased translation activity, accumulation of protein aggregation markers, and altered autophagy activity. To determine if altered H3K27me3 was responsible for this proteostasis dysregulation, we studied the effects of increased H3K27me3 by mutating the histone demethylase Utx. Reduced Utx activity enhanced neurodegeneration and mimicked the protein accumulation seen in miR-34 mutant brains. However, unlike the miR-34 mutant, Utx mutant brains did not show similar altered autophagy or translation activity, suggesting that additional miR-34-targeted pathways are involved. Transcriptional analysis of predicted miR-34 targets identified Lst8, a subunit of Tor Complex 1 (TORC1), as a potential target. We confirmed that miR-34 regulates the 3’ UTR of Lst8. Biological analysis of miR-34 mutant brains demonstrate that 4E-BP is hyperphosphorylated, consistent with increased Lst8 activity and changes in translation. Together, these results present novel understanding of brain aging and the role of the conserved miRNA miR-34 in impacting proteostasis in the brain with age.
2022-03-16 | GSE184559 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE24992: Drosophila brain microRNA expression with age: miRNA profiling GSE25007: Drosophila brain gene expression with age: mRNA profiling GSE25008: Drosophila brain gene expression between wildtype and miR-34 null flies Refer to individual Series. Aging is the most prominent risk factor for human neurodegenerative disease, but underlying mechanisms that connect two processes are less well characterized. With age, the brain undergoes functional decline and perhaps degeneration. Such decline may not just contribute to normal aging, but also enhance susceptibility to and progression of age-related neurodegenerative diseases. Therefore, defining intrinsic factors and pathways that underline the normal integrity of the adult nervous system may lead to insights that potentially link aging and neurodegeneration. Here, we report a highly conserved microRNA (miRNA), miR-34, as a modulator of aging and neurodegeneration. Using Drosophila, we show that fly miR-34 expression is brain-enriched and strikingly upregulated with age. Functional studies reveal that, whereas animals without miR-34 are normal as young adults, upon aging, they gradually show late-onset deficits characteristic of accelerated brain aging; these include a transcriptional signature of aged animals, coupled with rapid functional decline, loss of brain integrity, followed by a catastrophic decline in adult viability. Moreover, upregulation of miR-34 protects against neurodegeneration induced by pathogenic human polyglutamine (polyQ) disease protein. We next reveal a dramatic effect of miR-34 to silence the Eip74EF gene of steroid hormone pathways in the adult, which is crucial to maintain the normal aging. Collectively, these data define a miR-34-mediated mechanism that specifically affects long-term integrity of the adult nervous system. miR-34 function in Drosophila may thus present a link that functionally connects aging and neurodegeneration. Our studies implicate essential roles of miRNA- dependent pathways in maintenance of the adult brain, disease pathogenesis and healthy aging.
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