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Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression.

ABSTRACT: Alternative splicing of the gene MAPT produces several isoforms of tau protein. Overexpression of these isoforms is characteristic of tauopathies, which are currently untreatable neurodegenerative diseases. Though non-canonical functions of tau have drawn interest, the role of tau isoforms in these diseases has not been fully examined and may reveal new details of tau-driven pathology. In particular, tau has been shown to promote activation of transposable elements-highly regulated nucleotide sequences that replicate throughout the genome and can promote immunologic responses and cellular stress. This study examined tau isoforms' roles in promoting cell damage and dysregulation of genes and transposable elements at a family-specific and locus-specific level. We performed immunofluorescence, Western blot and cytotoxicity assays, along with paired-end RNA sequencing on differentiated SH-SY5Y cells infected with lentiviral constructs of tau isoforms and treated with amyloid-beta oligomers. Our transcriptomic findings were validated using publicly available RNA-sequencing data from Alzheimer's disease, progressive supranuclear palsy and control human samples from the Accelerating Medicine's Partnership for AD (AMP-AD). Significance for biochemical assays was determined using Wilcoxon ranked-sum tests and false discovery rate. Transcriptome analysis was conducted through DESeq2 and the TEToolkit suite available from the Hammell lab at Cold Spring Harbor Laboratory. Our analyses show overexpression of different tau isoforms and their interactions with amyloid-beta in SH-SY5Y cells result in isoform-specific changes in the transcriptome, with locus-specific transposable element dysregulation patterns paralleling those seen in patients with Alzheimer's disease and progressive supranuclear palsy. Locus-level transposable element expression showed increased dysregulation of L1 and Alu sites, which have been shown to drive pathology in other neurological diseases. We also demonstrated differences in rates of cell death in SH-SY5Y cells depending on tau isoform overexpression. These results demonstrate the importance of examining tau isoforms' role in neurodegeneration and of further examining transposable element dysregulation in tauopathies and its role in activating the innate immune system.

SUBMITTER: Grundman J

PROVIDER: S-EPMC8480850 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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.

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Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression.

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