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

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...

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Autores principales:	Jennifer Grundman, Brian Spencer, Floyd Sarsoza, Robert A Rissman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2db5286bb3dd42cc89e687069b57ad7b
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spelling	oai:doaj.org-article:2db5286bb3dd42cc89e687069b57ad7b2021-12-02T20:07:58ZTranscriptome analyses reveal tau isoform-driven changes in transposable element and gene expression.1932-620310.1371/journal.pone.0251611https://doaj.org/article/2db5286bb3dd42cc89e687069b57ad7b2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0251611https://doaj.org/toc/1932-6203Alternative 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.Jennifer GrundmanBrian SpencerFloyd SarsozaRobert A RissmanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0251611 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jennifer Grundman Brian Spencer Floyd Sarsoza Robert A Rissman Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression.
description	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.
format	article
author	Jennifer Grundman Brian Spencer Floyd Sarsoza Robert A Rissman
author_facet	Jennifer Grundman Brian Spencer Floyd Sarsoza Robert A Rissman
author_sort	Jennifer Grundman
title	Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression.
title_short	Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression.
title_full	Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression.
title_fullStr	Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression.
title_full_unstemmed	Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression.
title_sort	transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/2db5286bb3dd42cc89e687069b57ad7b
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Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression.

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