Loss of the long non-coding RNA, Malat1, accelerates premature aging and mortality
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ABSTRACT:
PROVIDER: PRJNA539976 | ENA |
REPOSITORIES: ENA
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Project description:Here we show that the 5’ end and 3’ end of Malat1 are dependently and independently expressed. Loss of 5’ Malat1 up-regulates Neat1 in cis, while loss of 3’ Malat1 globally regulated gene expression in trans. Furthermore, loss of 3’ Malat1 accelerates premature aging and shortens the lifespan in mice, but loss of 5’ Malat1 produces no phenotypic changes. Mechanistically, 3’ Malat1 exerts a tight regulation of P21 that is drastically up-regulated in brain and retina upon its deletion in mice. This is very likely mediated at two different levels. One is at the mRNA level since Malat1 interacts with hnRNP A1 and hnRNP A2/B1. This is independently of P53 since it is significantly decreased upon 3’ Malat1 KO, probably due to the down-regulation of hnRNP C which has been shown to maintain P53 mRNA stability in our cell line model. The other is at the protein level through NPM, which is significantly up-regulated in 3’ Malat1 KO and which was known to decrease P21 ubiquitination and hence stabilizing of P21. These observations reveal previously unknown functions of 3’ Malat in the brain and indicates the need for more detailed understanding of highly abundant conserved lncRNAs, such as Malat1, and alarms for detailed understanding before therapeutic targeting in the future.
2022-07-02 | GSE130392 | GEO
Project description:Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA) that was first discovered as a prognostic marker for lung cancer metastasis. MALAT1 has been implicated in the tumorigenesis of numerous tumor types. To further delineate the underlying molecular mechanism, we established a high-throughput strategy to characterize the interacting proteins of MALAT1 by combining RNA pull down, quantitative proteomics, bioinformatics analysis, and experimental validation.
2018-10-26 | PXD005154 | Pride
Project description:Alternative splicing (AS) of pre-mRNA is utilized by higher eukaryotes to achieve increased transcriptome and proteomic complexity. The serine/arginine (SR) splicing factors regulate tissue- or cell type-specific AS in a concentration and phosphorylation dependent manner. However, the mechanisms that modulate the cellular levels of active SR proteins remain to be elucidated. In the present study, we provide evidence for a role for the long nuclear-retained regulatory RNA (nrRNA), MALAT1 in AS regulation. MALAT1 interacts with SR proteins and influences the distribution of these and other splicing factors in nuclear speckle domains. Depletion of MALAT1 changes AS of endogenous pre-mRNAs, similar to what was observed upon overexpression of SR proteins. Furthermore, MALAT1 regulates cellular levels of phosphorylated forms of SR proteins. Taken together, our results suggest that MALAT1 regulates AS by modulating the levels of active SR proteins. Our results further highlight a novel role for a nrRNA in the regulation of gene expression. Malat1 Antisense and control knockdowns evaluated on a microarray platform to profile alternative splicing levels for 5782 cassette-type alternative exons.
2010-09-01 | E-GEOD-22963 | biostudies-arrayexpress
Project description:Previously, lncRNA Malat1 knockout mice were generated by insertional inactivation. By crossing this line to MMTV-PyMT mammary tumor mouse model, we produced PyMT;Malat1 wild-type (WT) and PyMT;Malat1 knockout (KO). Furthermore, we generated Malat1 transgenic mice by targeting ROSA26 locus and bred them to PyMT;Malat1 knockout mice to produce Malat1-rescued PyMT;Malat1 knockout;Malat1 transgenic animals (TG). Using mammary tumors from the three groups of animals, we performed RNA-Seq analysis to identify differentially up-regulated genes in KO tumors to find novel target genes of YAP-TEAD pathway.
2018-09-18 | GSE110239 | GEO
Project description:We collected sockeye salmon from the Fraser River, British Columbia, and held them at ecologically relevant temperatures (14C and 19C) determine the effect of elevated water temperature on cellular processes in non-lethally sampled gill tissue and blood plasma over a period of seven days that represents a significant portion of their upstream migration. Time-matched fish that died prematurely over the course of the holding study were also sampled for gill tissue and the transcriptomic responses in moribund fish were compared with surviving fish. This is the first study to experimentally examine transcriptomic responses to high water temperature and premature mortality in wild-caught Pacific salmon and the results will help in understanding some of the cellular mechanisms involved in large-scale migration mortality in Pacific salmon during warm water periods and for predicting or understanding causes of mortality in naturally senescing adult Pacific salmon. Forty samples were analyzed on forty two-channel microarrays, using a common reference design, with multiple biological replicates for each temperature condition. Fish were further classified into survivor and moribund based on their status after 7 days in captivity.
2012-05-30 | E-GEOD-33586 | biostudies-arrayexpress
Project description:Transposable elements (TEs) comprise a large proportion of long non-coding RNAs (lncRNAs). Here we employed CRISPR to delete a short interspersed nuclear element (SINE) in Malat1, a cancer-associated lncRNA, to investigate its significance in cellular physiology. We show that Malat1 with a SINE deletion forms diffuse nuclear speckles and is frequently translocated to the cytoplasm. SINE-deleted cells exhibit an activated unfolded protein response and PKR and markedly increased DNA damage and apoptosis caused by dysregulation of TDP-43 localization and formation of cytotoxic inclusions. TDP-43 binds stronger to Malat1 without the SINE and is likely ”hijacked” by cytoplasmic Malat1 to the cytoplasm, resulting in the depletion of nuclear TDP-43 and redistribution of TDP-43 binding to repetitive element transcripts and mRNAs encoding mitotic and nuclear-cytoplasmic regulators. The SINE promotes Malat1 nuclear retention by facilitating Malat1 binding to HNRNPK, a protein that drives RNA nuclear retention, potentially through direct interactions of the SINE with KHDRBS1 and TRA2A, which bind to HNRNPK. Losing these RNA-protein interactions due to the SINE deletion likely creates more available TDP-43 binding sites on Malat1 and subsequent TDP-43 aggregation. These results highlight the significance of lncRNA TEs in TDP-43 proteostasis with potential implications in both cancer and neurodegenerative diseases.
2019-12-03 | GSE141303 | GEO
Project description:Since we found an upregulation of the long non coding RNA MALAT1 in Multiple Sclerosis (MS) patients, we decided to explore the global effect of MALAT1 modulation on transcriptome. We hence performed high-coverage RNA-seq experiments of MALAT1 knockdown in Jurkat E6-1 T cells to analyze gene expression, alternative splicing (AS), and backsplicing profiles. We found 107 differentially expressed genes, 1114 dysregulated AS events, and 49 circular RNAs that were modulated by MALAT1. These results highlighted the role of MALAT1 in splicing and backsplicing regulation.
2019-01-15 | GSE110525 | GEO
Project description:Malat1 is an abundant long noncoding RNA that localizes to nuclear bodies known as nuclear speckles, which contain a distinct set of pre-mRNA processing factors. Previous in vitro studies have demonstrated that Malat1 interacts with pre-mRNA splicing factors, including the serine- and arginine-rich (SR) family of proteins, and regulates a variety of biological processes, including cancer cell migration, synapse formation, cell cycle progression, and responses to serum stimulation. To address the physiological function of Malat1 in a living organism, we generated Malat1-KO (KO) mice using homologous recombination. Unexpectedly, the Malat1-KO mice were viable and fertile, showing no apparent phenotypes. Nuclear speckle markers were also correctly localized in cells that lacked Malat1. However, the cellular levels of another long noncoding RNA, Neat1, which is an architectural component of nuclear bodies known as paraspeckles, were downregulated in a particular set of tissues and cells lacking Malat1. To address if the the absence of Malat1 affects the expression of other genes, including other long noncoding RNA, microarrays were used to study the impact of knocking-out Malat1 on global gene expression in mouse embryonic fibroblasts (MEFs). MEFs were prepared from E13.5 mouse embryos from wildtype and Malat1 knock-out mice. RNA harvested from these cells were hybridized to Affymetirx mouse gene expression array.
2012-06-24 | E-GEOD-37705 | biostudies-arrayexpress
Project description:We collected sockeye salmon from the Fraser River, British Columbia, and held them at ecologically relevant temperatures (14C and 19C) determine the effect of elevated water temperature on cellular processes in non-lethally sampled gill tissue and blood plasma over a period of seven days that represents a significant portion of their upstream migration. Time-matched fish that died prematurely over the course of the holding study were also sampled for gill tissue and the transcriptomic responses in moribund fish were compared with surviving fish. This is the first study to experimentally examine transcriptomic responses to high water temperature and premature mortality in wild-caught Pacific salmon and the results will help in understanding some of the cellular mechanisms involved in large-scale migration mortality in Pacific salmon during warm water periods and for predicting or understanding causes of mortality in naturally senescing adult Pacific salmon.
2012-05-31 | GSE33586 | GEO
Project description:Malat1 is an abundant long noncoding RNA that localizes to nuclear bodies known as nuclear speckles, which contain a distinct set of pre-mRNA processing factors. Previous in vitro studies have demonstrated that Malat1 interacts with pre-mRNA splicing factors, including the serine- and arginine-rich (SR) family of proteins, and regulates a variety of biological processes, including cancer cell migration, synapse formation, cell cycle progression, and responses to serum stimulation. To address the physiological function of Malat1 in a living organism, we generated Malat1-KO (KO) mice using homologous recombination. Unexpectedly, the Malat1-KO mice were viable and fertile, showing no apparent phenotypes. Nuclear speckle markers were also correctly localized in cells that lacked Malat1. However, the cellular levels of another long noncoding RNA, Neat1, which is an architectural component of nuclear bodies known as paraspeckles, were downregulated in a particular set of tissues and cells lacking Malat1. To address if the absence of Malat1 affects the expression of other genes, including other long noncoding RNA, microarrays were used to study the impact of knocking-out Malat1 on global gene expression in hippocampal neurons. Hippocampi were dissected from two sets of wildtype and Malat1 knock-out mice and RNA from these neurons were hybridized to Affymetix mouse exon array. Individual animals from each pairs of wildtype and knock-out are littermates.
2012-06-24 | E-GEOD-37706 | biostudies-arrayexpress