Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies
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ABSTRACT:
PROVIDER: PRJNA475562 | ENA |
REPOSITORIES: ENA
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Project description:Transposable elements, known colloquially as “jumping genes,” constitute approximately 45% of the human genome. Cells utilize epigenetic defenses to limit transposable element jumping, including formation of silencing heterochromatin and generation of piwi-interacting RNAs (piRNAs), small RNAs that facilitate clearance of transposable element transcripts. Here we identify transposable element activation as a key mediator of neuronal death in tauopathies, a group of neurodegenerative disorders, including Alzheimer’s disease, that are pathologically characterized by deposits of tau protein in the brain. Mechanistically, we find that heterochromatin decondensation and reduction of piwi/piRNAs drive transposable element activation in tauopathy. Using genetic and pharmacological approaches in a Drosophila melanogaster model of tauopathy, we provide evidence for a causal relationship between pathogenic tau-induced heterochromatin decondensation, piwi/piRNA depletion, active transposable element obilization, and neurodegeneration. We further report a significant increase in transcripts of the endogenous retrovirus class of transposable elements in human Alzheimer’s disease and progressive supranuclear palsy, suggesting that transposable element dysregulation is conserved in human tauopathy. Taken together, our data identify heterochromatin decondensation, piwi/piRNA depletion and consequent transposable element activation as a novel, pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy.
2018-07-04 | GSE115606 | GEO
Project description: Not available
| S-EPMC6095477 | biostudies-literature
Project description:Purpose: Overexpression of tau isoforms has been linked to neurodegenerative diseases, and abnormal tau expression is correlated with genomic instability. The purpose of this study is to use RNA-sequencing and molecular biological techniques to determine if there are any unique genomic consequences associated with overexpression of one or more tau isoforms. Methods: SHSY-5Y cells were infected in triplicate with lentiviruses to induce overexpression of 3R and 4R tau isoforms, were treated with amyloid-beta oligomers or DMSO, and were differentiated into neurons using retinoic acid. After RNA collection via TRIzol, poly(A)-selected, 100 bp, paired-end library preparation and sequencing were completed by the IGM Genomics Center, University of California, San Diego, La Jolla, CA, using an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929). Trimmed FASTQ files were aligned to GRCH38 using STAR and differential expression of genes and transposable elements was determined using DESeq2 and software from TEToolkit (available from the Hammell Lab at Cold Spring Harbor Laboratory). Results: Our RNA-seq analysis revealed similar gene and transposable element expression patterns between cells overexpressing tau isoforms and patients with Alzheimer's disease or progressive supranuclear palsy. We found widespread differential expression particularly in L1 and Alu transposable elements and upregulation of genes related to extracellular matrix organization, focal adhesions, and cell junctions, among other biological processes. Conclusions: Our study is the first to our knowledge to examine locus-specific transposable element expression in the context of tauopathies, and to our knowledge is the first to specifically examine transposable element expression stemming from overexpression of tau isoforms. Our study provides additional evidence that transposable elements may play a role in tauopathies and provides further insight into the locations of transposable element expression in the genome in the context of neurodegenerative diseases.
2021-09-12 | GSE163150 | GEO
Project description:Background: The small RNAs that Transposable Elements generate are vastly different when they are transcriptionally silenced compared to when they are transcriptionally activated. We performed the deep sequencing of small RNAs in a number of small RNA biogenesis mutants in both Transposable Element-silenced and Transposable Element-active epigenome backgrounds. Results: We found that Transposable Elements generate large amounts of 21-22nt siRNAs only when they are transcriptionally active. These 21-22nt siRNAs are incorporated into the AGO6 protein. Conclusion: Ago6 is the key protein that bridges the post-transcriptional degradation of Transposable Element mRNAs and the establishment of DNA methylation. Examination of flower bud small RNAs from wild type and 5 single or double mutant combinations, many of which have biological replicates. In addition, IP purification of the AGO6 protein (and mock no-antigen controls) followed by sequencing of the incorporated small RNAs. Replicate A for Col and ddm1 are submitted in GSE41755
2014-11-14 | E-GEOD-57191 | biostudies-arrayexpress
Project description:Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression
| PRJNA685110 | ENA
Project description:Background: The small RNAs that Transposable Elements generate are vastly different when they are transcriptionally silenced compared to when they are transcriptionally activated. We performed the deep sequencing of small RNAs in a number of small RNA biogenesis mutants in both Transposable Element-silenced and Transposable Element-active epigenome backgrounds. Results: We found that Transposable Elements generate large amounts of 21-22nt siRNAs only when they are transcriptionally active. These 21-22nt siRNAs are incorporated into the AGO6 protein. Conclusion: Ago6 is the key protein that bridges the post-transcriptional degradation of Transposable Element mRNAs and the establishment of DNA methylation.
2014-11-14 | GSE57191 | GEO
Project description: Not available
| S-EPMC6573471 | biostudies-literature
Project description:Many RNA-binding proteins (RBPs), particularly those associated with RNA granules, promote pathological protein aggregation in neurodegenerative diseases. Here, we demonstrate that G3BP2, a core component of stress granules, directly interacts with Tau and inhibits Tau aggregation. In the human brain, the interaction of G3BP2 and Tau is dramatically increased in multiple Tauopathies and precedes neurofibrillary tangle (NFT) formation in Alzheimer’s disease (AD). Surprisingly, Tau pathology is significantly elevated upon loss of G3BP2 in human neurons and brain organoids. Moreover, we find that G3BP2 masks the microtubule-binding region (MTBR) of Tau, thereby inhibiting Tau aggregation. Our study defines a novel role for RBPs as a line of defense against Tau aggregation in Tauopathies.
2023-05-17 | GSE226624 | GEO
Project description:Tau (MAPT) is a microtubule-associated protein causing frequent neurodegenerative diseases or inherited frontotemporal lobar degenerations. Emerging evidence for non-canonical functions of Tau in DNA protection and P53 regulation suggests its involvement in cancer. Indeed, Tau expression correlates with cancer-specific survival or response to microtubule therapeutics. These data may imply common molecular pathways involved in the pathogenesis of neurodegenerative disorders and cancer. To bring new evidence that Tau represents a key protein in cancer, we present an in silico pan-cancer analysis of MAPT transcriptomic profile in over 11000 clinical samples and over 1300 pre-clinical samples provided by the TCGA and the DEPMAP datasets respectively. We completed this analysis by exploring a possible interplay of MAPT with wild-type or mutated P53. Then, we calculated the impact of MAPT expression on clinical outcome and drug response. Overall, the results support a relevant role of the MAPT gene in several cancer types, although the contribution of Tau to cancer appears to very much depend on the cellular context.
2022-11-27 | E-MTAB-8166 | biostudies-arrayexpress
Project description:Background: Transposable element 24 nucleotide small RNAs are not efficiently incorporated into the AGO1 protein, which is involved in endogenous RNAi and gene regulation through the microRNA and tasiRNA pathways. Results: The AGO1 protein incorporates large quantities of transposable element siRNAs when transposable elements are epigenetically activated and transcribed. The incorporation of transposable element siRNAs is at the expense of the most abundant microRNAs. These transposable element siRNAs can act as tasiRNAs, regulating genes that they have partial complementarity to. Conclusion: Transposable element small RNAs are more dynamic than previously thought. They can be incorporated into AGO1 and regulate genes. Three biological replicates of small RNA sequencing from two genotypes
2014-04-07 | E-GEOD-45990 | biostudies-arrayexpress