Effects of HOE-1 (RNase Z/ELAC2) nuclear hyperactivation on gene expression in Caenorhabditis elegans.
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ABSTRACT:
PROVIDER: PRJNA1087453 | ENA |
REPOSITORIES: ENA
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Project description:We previously reported that the RNA endonculease HOE-1 (RNaseZ/ELAC2) is necessary and sufficient for activation of the mitochondrial unfolded protein response (UPRmt) in C. elegans (PMID: 35451962). To comprehensively assess the broader cellular consequences of increased nuclear activity of HOE-1, we conducted RNA sequencing on day 2 adult wildtype animals vs animals in which endogenous HOE-1 is elevated in the nucleus via perturbation of its nuclear export signal (hoe-1(ΔNES)). Additionally, wildtype and hoe-1(ΔNES) animals were grown on both control and atfs-1 RNAi (ATFS-1 is the central transcription factor for UPRmt) to determine gene expression that is atfs-1 dependent. This analysis revealed that differential gene expression in hoe-1(ΔNES) animals exhibits a strong mitochondrial signature. Notably, gene ontology (GO) analysis of significantly upregulated genes showed a significant overrepresentation of mitochondrial associated genes. Moreover, knockdown of atfs-1 strongly compromised the differentially expressed gene profile. Together these data suggest that increased nuclear activity of HOE-1 preferential impacts expression of mitochondrial genes.
2024-03-13 | GSE261565 | GEO
Project description:Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer deaths in men. GWAS studies have identified variants associated with prostate cancer susceptibility, however, mechanistic and functional validation of these mutations are lacking. Mitochondrial energy metabolism plays an important role in the onset and development of cancer. A missense variant was identified in the ELAC2 gene, which encodes a dually localized nuclear and mitochondrial RNA processing enzyme, with predicted impact on metabolism and tumorigenesis. We used CRISPR/Cas9 genome editing to introduce this variant into the mouse Elac2 gene as well as to generate a prostate-specific gene knockout of Elac2. The mutations caused enlargement and inflammation in the prostate and nodule formation. Multi-omic profiling revealed defects in RNA and energy metabolism that activated proinflammatory and tumorigenic pathways as a consequence of impaired processing of mitochondrial and nuclear encoded non-coding RNAs and reduced protein synthesis. The Elac2 variant or knockout mice on the background of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model show that Elac2 mutation with a secondary genetic insult exacerbated the onset and progression of prostate cancer and led to metastasis. Our systems biology analyses reveal a miRNA-mediated molecular mechanism by which specific non-coding RNAs elicit metabolic changes that drive prostate tumorigenesis and metastasis. We conclude that this ELAC2 variant is a predisposing factor for prostate cancer and provide a detailed molecular mechanism and physiologically relevant models of this cancer.
2023-03-21 | GSE201181 | GEO
Project description:Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer deaths in men. GWAS studies have identified variants associated with prostate cancer susceptibility, however, mechanistic and functional validation of these mutations are lacking. Mitochondrial energy metabolism plays an important role in the onset and development of cancer. A missense variant was identified in the ELAC2 gene, which encodes a dually localized nuclear and mitochondrial RNA processing enzyme, with predicted impact on metabolism and tumorigenesis. We used CRISPR/Cas9 genome editing to introduce this variant into the mouse Elac2 gene as well as to generate a prostate-specific gene knockout of Elac2. The mutations caused enlargement and inflammation in the prostate and nodule formation. Multi-omic profiling revealed defects in RNA and energy metabolism that activated proinflammatory and tumorigenic pathways as a consequence of impaired processing of mitochondrial and nuclear encoded non-coding RNAs and reduced protein synthesis. The Elac2 variant or knockout mice on the background of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model show that Elac2 mutation with a secondary genetic insult exacerbated the onset and progression of prostate cancer and led to metastasis. Our systems biology analyses reveal a miRNA-mediated molecular mechanism by which specific non-coding RNAs elicit metabolic changes that drive prostate tumorigenesis and metastasis. We conclude that this ELAC2 variant is a predisposing factor for prostate cancer and provide a detailed molecular mechanism and physiologically relevant models of this cancer.
2023-03-21 | GSE201183 | GEO
Project description:Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer deaths in men. GWAS studies have identified variants associated with prostate cancer susceptibility, however, mechanistic and functional validation of these mutations are lacking. Mitochondrial energy metabolism plays an important role in the onset and development of cancer. A missense variant was identified in the ELAC2 gene, which encodes a dually localized nuclear and mitochondrial RNA processing enzyme, with predicted impact on metabolism and tumorigenesis. We used CRISPR/Cas9 genome editing to introduce this variant into the mouse Elac2 gene as well as to generate a prostate-specific gene knockout of Elac2. The mutations caused enlargement and inflammation in the prostate and nodule formation. Multi-omic profiling revealed defects in RNA and energy metabolism that activated proinflammatory and tumorigenic pathways as a consequence of impaired processing of mitochondrial and nuclear encoded non-coding RNAs and reduced protein synthesis. The Elac2 variant or knockout mice on the background of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model show that Elac2 mutation with a secondary genetic insult exacerbated the onset and progression of prostate cancer and led to metastasis. Our systems biology analyses reveal a miRNA-mediated molecular mechanism by which specific non-coding RNAs elicit metabolic changes that drive prostate tumorigenesis and metastasis. We conclude that this ELAC2 variant is a predisposing factor for prostate cancer and provide a detailed molecular mechanism and physiologically relevant models of this cancer.
2023-03-21 | GSE201182 | GEO
Project description:The molecular roles of the dually targeted ElaC domain protein 2 (ELAC2) during nuclear and mitochondrial RNA processing in vivo have not been distinguished. We generated conditional knockout mice of ELAC2 to identify that it is essential for life and its activity is non-redundant. Heart and skeletal muscle-specific loss of ELAC2 causes dilated cardiomyopathy and premature death at 4 weeks. Transcriptome-wide analyses of total RNAs, small RNAs, mitochondrial RNAs and miRNAs identified the nuclear and mitochondrial molecular targets of ELAC2 in vivo. We show that ELAC2 is required for processing of nuclear and mitochondrial tRNAs and for the balanced maintenance of C/D box snoRNAs, a new class of tRNA fragments, and miRNAs. We identify that correct biogenesis of regulatory non-coding RNAs is essential for both cytoplasmic and mitochondrial protein synthesis as well as the assembly of mitochondrial ribosomes and cytoplasmic polysomes. Taken together our data show that nuclear tRNA processing is required for the balanced production of snoRNAs and miRNAs for gene expression and that 3′ tRNA processing follows 5′ tRNA processing but nevertheless is an essential step in the production of all mature mitochondrial RNAs and the majority of nuclear tRNAs.
2018-08-20 | GSE111226 | GEO
Project description:The molecular roles of the dually targeted ElaC domain protein 2 (ELAC2) during nuclear and mitochondrial RNA processing in vivo have not been distinguished. We generated conditional knockout mice of ELAC2 to identify that it is essential for life and its activity is non-redundant. Heart and skeletal muscle-specific loss of ELAC2 causes dilated cardiomyopathy and premature death at 4 weeks. Transcriptome-wide analyses of total RNAs, small RNAs, mitochondrial RNAs and miRNAs identified the nuclear and mitochondrial molecular targets of ELAC2 in vivo. We show that ELAC2 is required for processing of nuclear and mitochondrial tRNAs and for the balanced maintenance of C/D box snoRNAs, a new class of tRNA fragments, and miRNAs. We identify that correct biogenesis of regulatory non-coding RNAs is essential for both cytoplasmic and mitochondrial protein synthesis as well as the assembly of mitochondrial ribosomes and cytoplasmic polysomes. Taken together our data show that nuclear tRNA processing is required for the balanced production of snoRNAs and miRNAs for gene expression and that 3′ tRNA processing follows 5′ tRNA processing but nevertheless is an essential step in the production of all mature mitochondrial RNAs and the majority of nuclear tRNAs.
2018-08-20 | GSE111225 | GEO
Project description:The molecular roles of the dually targeted ElaC domain protein 2 (ELAC2) during nuclear and mitochondrial RNA processing in vivo have not been distinguished. We generated conditional knockout mice of ELAC2 to identify that it is essential for life and its activity is non-redundant. Heart and skeletal muscle-specific loss of ELAC2 causes dilated cardiomyopathy and premature death at 4 weeks. Transcriptome-wide analyses of total RNAs, small RNAs, mitochondrial RNAs and miRNAs identified the nuclear and mitochondrial molecular targets of ELAC2 in vivo. We show that ELAC2 is required for processing of nuclear and mitochondrial tRNAs and for the balanced maintenance of C/D box snoRNAs, a new class of tRNA fragments, and miRNAs. We identify that correct biogenesis of regulatory non-coding RNAs is essential for both cytoplasmic and mitochondrial protein synthesis as well as the assembly of mitochondrial ribosomes and cytoplasmic polysomes. Taken together our data show that nuclear tRNA processing is required for the balanced production of snoRNAs and miRNAs for gene expression and that 3′ tRNA processing follows 5′ tRNA processing but nevertheless is an essential step in the production of all mature mitochondrial RNAs and the majority of nuclear tRNAs.
2018-08-20 | GSE111227 | GEO
Project description:Identification of in vivo binding targets of Met4 and Met32 by conducting chromatin immunoprecipitation studies using genomic tiling arrays (ChIP-on-chip 4X44K whole yeast genome arrays by Agilent) following 90 minutes Met4 hyperactivation.
2012-02-21 | E-MEXP-3302 | biostudies-arrayexpress
Project description:This project aims to identify novel RNA binding proteins in the nematode, Caenorhabditis elegans. Since interactions between RNAs and proteins may be transient, these animals were crosslinked with UV light at 254 nm which promotes the covalent link between proteins and RNAs. After this, polyadenylated mRNAs were purified via oligo(dT) coupled to magentic beads under stringent conditions. Finally, samples were subjected to mass spectrometry analysis. To rule out the possibility of RNA-independent binding we also analysed other samples: i) samples digested with RNase one; ii) samples where we performed competition assays with polyadenylic acid
2015-10-26 | PXD002226 | Pride
Project description:RNase Z is an endonuclease responsible for the removal of 3' extensions from tRNA precursors, an essential step in tRNA biogenesis. Human cells contain a long form (RNase Z(L)) encoded by ELAC2, and a short form (RNase Z(S); ELAC1). We studied their subcellular localization by expression of proteins fused to green fluorescent protein. RNase Z(S) was found in the cytosol, whereas RNase Z(L) localized to the nucleus and mitochondria. We show that alternative translation initiation is responsible for the dual targeting of RNase Z(L). Due to the unfavorable context of the first AUG of ELAC2, translation apparently also starts from the second AUG, whereby the mitochondrial targeting sequence is lost and the protein is instead routed to the nucleus. Our data suggest that RNase Z(L) is the enzyme involved in both, nuclear and mitochondrial tRNA 3' end maturation.
| S-EPMC3084753 | biostudies-literature