Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MLL RIP-seq

ABSTRACT: We uncovered an unexpected function of mixed-lineage leukemia (MLL) protein, which is a critical epigenetic factor and whose disruption leads to leukemogenesis, in the functional regulation of miRNAs. We reveal that the MLLC180 subunit alone can colocalize with miRNA-induced silencing complex (miRISC) components in cytoplasm processing bodies (P-bodies), where miRNA-mediated gene silencing takes place. In addition, we show that MLL was specifically required for miRNA-mediated translational repression, but not for miRNA or siRNA-mediated mRNA cleavage. Mechanistically, MLL was necessarily required for recruiting miRNA to the miRISC and P-body core, partly through its binding partner RAN. Furthermore, dysregulation of the miRNA repression function in MLL leukemic cells was essential for high-level expression of MYC, which ensured the survival of MLL leukemic cells. Thus, our investigation discovered that the MLL subunit alone can exert other functions in miRNA-mediated gene silencing apart from the epigenetic function of the whole MLL heterodimer. We also demonstrated as proof-of-principle that functional deregulation of miRNA may play an important role in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115848 | GEO | 2020/01/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

RAB protein controls Argonaute localization for proper miRNA function in C. elegans

Project description:MicroRNAs are critical regulators of gene expression in animals. To repress their target mRNAs, these small RNAs are first loaded onto Argonaute proteins to form the silencing complex called miRISC. The complex must then be transported to its target mRNA where it interacts mostly within the 3’UTR through base-pairing. After target repression, the constituents of the miRISC undergo degradation or recycling mediated through their accurate sorting and localization in the cell. While some reports have linked intracellular trafficking to miRNA activity, it is still unclear how these pathways coordinate to allow proper miRNA-mediated gene silencing and turnover. Through a forward genetic screen performed in the nematode Caenorhabditis elegans, we identified the RabGAP tbc-11 as an important factor for the miRNA pathway. We show that TBC-11 is likely a GAP for the small GTPase RAB-6 and that its regulation is required for miRNA function in animals. The absence of functional TBC-11 leads to the persistent activation of RAB-6, which increases the localization of miRNA-unloaded Argonaute ALG-1 on endomembranes. This inactive form of Argonaute accumulates on polysomes, leading to defective miRNA-mediated target mRNA repression. Together, our results establish the importance of intracellular trafficking for miRNA function and demonstrates the involvement of a small GTPase in proper Argonaute localization in vivo.

2021-03-16 | GSE141719 | GEO

Translation is required for miRNA-dependent decay of endogenous transcripts.

Project description:Posttranscriptional repression by microRNA (miRNA) occurs through transcript destabilization or translation inhibition. Whereas RNA degradation explains most miRNA-dependent repression, transcript decay occurs co-translationally, raising questions regarding the requirement of target translation to miRNA-dependent transcript destabilization. To assess the contribution of translation to miRNA-mediated RNA destabilization, we decoupled these two molecular processes by dissecting the impact of miRNA loss of function on cytosolic long noncoding RNAs (lncRNAs). We show, that despite interacting with miRNA loaded RNA-induced silencing complex (miRISC), the steady state abundance and degradation rates of these endogenously expressed non-translated transcripts are minimally impacted by miRNA loss. To validate the requirement of translation to miRNA-dependent decay, we fused a miRISC bound lncRNA, whose levels are unaffected by miRNAs, to the 3’end of a protein-coding gene reporter and shown that this results in its miRNA-dependent transcript destabilization. Furthermore, analysis of the few lncRNAs whose levels are regulated by miRNAs revealed these tend to associate with translating ribosomes and are likely misannotated micropeptides, further substantiating the necessity of target translation to miRNA-dependent transcript decay. Our analyses revealed the strict requirement of translation for miRNA-dependent transcript destabilization and demonstrates that the levels of coding and noncoding transcripts are differently affected by miRNAs.

2020-01-09 | GSE143277 | GEO

Arabidopsis AGO1 N-terminal Poly-Q domain promotes phase separation and association with stress granules during heat stress

Project description:In Arabidopsis thaliana, ARGONAUTE1 (AGO1) plays a central role in microRNA (miRNA) and small interfering RNA (siRNA)-mediated silencing. Nuclear AGO1 is loaded with miRNAs and exported to the cytosol where it associates to the rough ER to conduct miRNA-mediated translational repression, mRNA cleavage and biogenesis of phased siRNAs. These latter, as well as other cytosolic siRNAs, are loaded into cytosolic AGO1, but in which compartment this happens is not known. Moreover, the effect of stress on AGO1 localization is still unclear. Here, we show that heat stress (HS) promotes AGO1 protein accumulation, which co-localize with components of the siRNA bodies and of stress granules (SGs). AGO1 does not need SGS3, a key component of siRNA bodies, to efficiently form condensates during HS. Instead, we found that the still poorly characterized N-terminal Poly-Q domain of AGO1, which contains a prion-like domain, is sufficient to undergo phase separation. Moreover, an exposure of 1 hour to HS only moderately affected AGO1 loading by miRNAs and target cleavage, suggesting that its localization in condensates protects AGO1 rather than promote its activity in reprograming gene expressing during stress. Collectively, our work shed new light on the impact of high temperature on a main effector of RNA silencing in plants.

2024-06-22 | PXD048594 | Pride

Genome-wide analysis of miRNA-targeted cellular NMD substrates in HeLa cell

Project description:Analysis of miRNA-targeted cellular NMD substrates in HeLa cell. The hypothesis tested in the present study was that endogenous NMD substrates containing long 3' untranslated region may targeted for miRNA. Results provide important information expanding the roles of miRISC in the posttranscriptional regulation of gene expression: a new cross-talk between miRNA-mediated gene silencing and NMD. ABSTRACT: Imperfect base-pairing between microRNA (miRNA) and the 3â-untranslated region (3âUTR) of target mRNA triggers translational repression of the target mRNA. Here, we provide evidence that human Argonaute 2 (Ago2) targets cap-binding protein (CBP)80/20- and exon junction complex (EJC)-bound mRNAs and inhibits nonsense-mediated mRNA decay (NMD), which is tightly restricted to CBP80/20-bound mRNAs. Furthermore, microarray analyses reveal that a subset of cellular transcripts, which are expected to be targeted for NMD, is stabilized by miRNA-mediated gene silencing. The regulation of NMD by miRNAs will shed light on a new post-transcriptional regulation mechanism of gene expression in mammalian cells Total RNA obtained from HeLa cells with downregulation of Ago2 or Ago2/UPF1 by siRNA. The up- or down-regulated transcripts were compared to control siRNA treated HeLa cell RNA extract. Significant transcripts were confirmed by replication.

2010-04-09 | E-GEOD-16170 | biostudies-arrayexpress

Genome-wide analysis of miRNA-targeted cellular NMD substrates in HeLa cell

Project description:Analysis of miRNA-targeted cellular NMD substrates in HeLa cell. The hypothesis tested in the present study was that endogenous NMD substrates containing long 3' untranslated region may targeted for miRNA. Results provide important information expanding the roles of miRISC in the posttranscriptional regulation of gene expression: a new cross-talk between miRNA-mediated gene silencing and NMD. ABSTRACT: Imperfect base-pairing between microRNA (miRNA) and the 3’-untranslated region (3’UTR) of target mRNA triggers translational repression of the target mRNA. Here, we provide evidence that human Argonaute 2 (Ago2) targets cap-binding protein (CBP)80/20- and exon junction complex (EJC)-bound mRNAs and inhibits nonsense-mediated mRNA decay (NMD), which is tightly restricted to CBP80/20-bound mRNAs. Furthermore, microarray analyses reveal that a subset of cellular transcripts, which are expected to be targeted for NMD, is stabilized by miRNA-mediated gene silencing. The regulation of NMD by miRNAs will shed light on a new post-transcriptional regulation mechanism of gene expression in mammalian cells

2010-03-08 | GSE16170 | GEO

Modeling neurodevelopmental disorder-associated human AGO1 mutations in C. elegans Argonaute alg-1. [RNA-Seq]

Project description:MicroRNAs (miRNA) associate with Argonaute proteins and negatively regulate gene expression by base pairing with complementary sequences in the 3’ UTRs of target genes. De novo coding variants in the human Argonaute gene AGO1 were reported to cause neurodevelopmental disorder (NDD) with intellectual disability (ID). Most of the altered amino acids are conserved between the miRNA associated Argonautes in H. sapiens and C. elegans, suggesting that the human AGO1 mutations could disrupt evolutionarily conserved functions in miRNA biogenesis or target repression. We genetically modeled four human AGO1 mutations in C. elegans by introducing identical mutations into the C. elegans AGO1 homolog, ALG-1. These alg-1 NDD mutations caused phenotypes in C. elegans indicative of disrupted miRNA processing, miRISC formation, and/or target repression. We show that the alg-1 NDD mutations are antimorphic as they cause developmental and molecular phenotypes stronger than those exhibited by the alg-1 null mutants, likely by sequestrating functional miRNA silencing complex (miRISC) components into non-functional complexes that fail to confer robust gene repression. The alg-1 NDD mutations cause allele-specific disruptions in mature miRNA profiles, both in overall abundances and ALG-1 NDD association, accompanied by perturbation of downstream gene expression, including altered translational efficiency and/or mRNA abundance. The perturbed genes include those with human orthologs whose dysfunction is associated with NDD. These cross-clade genetic studies illuminate fundamental Argonaute functions and provide insights into the conservation of miRNA-mediated post-transcriptional regulatory mechanisms.

2023-12-30 | GSE252065 | GEO

Modeling neurodevelopmental disorder-associated human AGO1 mutations in C. elegans Argonaute alg-1. [smallRNA-Seq]

2023-12-30 | GSE252064 | GEO

Modeling neurodevelopmental disorder-associated human AGO1 mutations in C. elegans Argonaute alg-1. [ribosome profiling]

2023-12-30 | GSE252063 | GEO

Expression data from HEK 293T cells overexpressing either myc-FUS or myc-R495X (exon)

Project description:Individuals with the ALS-linked (amyotrophic lateral sclerosis) truncation mutation (R495X) in FUS (fused in sarcoma) are known to have a more aggressive form of the disease than those with point mutations. The underlying cause for this difference is unclear. We report that FUS is a component of miRISC (miRNA-induced silencing complex) and that overexpression of its truncation mutant R495X negatively impacts miRNA mediated RNA silencing. In this study, we compared the impact overexpression of wild-type myc-tagged FUS versus truncation mutant R495X has on global gene expression.

2018-03-14 | GSE68501 | GEO

Expression data from HEK 293T cells overexpressing either myc-FUS or myc-R495X (miRNA)

2018-03-14 | GSE68502 | GEO