Tau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes

Tau protein is a known contributor in several neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). It is well-established that tau forms pathological aggregates and fibrils in these diseases. Tau has been observed within the nuclei of neurons, but there i...

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Autores principales:	Mauro Montalbano, Elizabeth Jaworski, Stephanie Garcia, Anna Ellsworth, Salome McAllen, Andrew Routh, Rakez Kayed
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	alternative polyadenylation frontal temporal dementia gene ontology gene set enrichment analysis tau neurodegenaration Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/e82630aa9dc645a094f19b3dcebd97b6
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spelling	oai:doaj.org-article:e82630aa9dc645a094f19b3dcebd97b62021-12-03T06:25:29ZTau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes1662-509910.3389/fnmol.2021.742790https://doaj.org/article/e82630aa9dc645a094f19b3dcebd97b62021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnmol.2021.742790/fullhttps://doaj.org/toc/1662-5099Tau protein is a known contributor in several neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). It is well-established that tau forms pathological aggregates and fibrils in these diseases. Tau has been observed within the nuclei of neurons, but there is a gap in understanding regarding the mechanism by which tau modulates transcription. We are interested in the P301L mutation of tau, which has been associated with FTD and increased tau aggregation. Our study utilized tau-inducible HEK (iHEK) cells to reveal that WT and P301L tau distinctively alter the transcription and alternative polyadenylation (APA) profiles of numerous nuclear precursors mRNAs, which then translate to form proteins involved in chromatin remodeling and splicing. We isolated total mRNA before and after over-expressing tau and then performed Poly(A)-ClickSeq (PAC-Seq) to characterize mRNA expression and APA profiles. We characterized changes in Gene Ontology (GO) pathways using EnrichR and Gene Set Enrichment Analysis (GSEA). We observed that P301L tau up-regulates genes associated with reactive oxygen species responsiveness as well as genes involved in dendrite, microtubule, and nuclear body/speckle formation. The number of genes regulated by WT tau is greater than the mutant form, which indicates that the P301L mutation causes loss-of-function at the transcriptional level. WT tau up-regulates genes contributing to cytoskeleton-dependent intracellular transport, microglial activation, microtubule and nuclear chromatin organization, formation of nuclear bodies and speckles. Interestingly, both WT and P301L tau commonly down-regulate genes responsible for ubiquitin-proteosome system. In addition, WT tau significantly down-regulates several genes implicated in chromatin remodeling and nucleosome organization. Although there are limitations inherent to the model systems used, this study will improve understanding regarding the nuclear impact of tau at the transcriptional and post-transcriptional level. This study also illustrates the potential impact of P301L tau on the human brain genome during early phases of pathogenesis.Mauro MontalbanoMauro MontalbanoElizabeth JaworskiStephanie GarciaStephanie GarciaAnna EllsworthAnna EllsworthSalome McAllenSalome McAllenAndrew RouthAndrew RouthRakez KayedRakez KayedFrontiers Media S.A.articlealternative polyadenylationfrontal temporal dementiagene ontologygene set enrichment analysistauneurodegenarationNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Molecular Neuroscience, Vol 14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	alternative polyadenylation frontal temporal dementia gene ontology gene set enrichment analysis tau neurodegenaration Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	alternative polyadenylation frontal temporal dementia gene ontology gene set enrichment analysis tau neurodegenaration Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Mauro Montalbano Mauro Montalbano Elizabeth Jaworski Stephanie Garcia Stephanie Garcia Anna Ellsworth Anna Ellsworth Salome McAllen Salome McAllen Andrew Routh Andrew Routh Rakez Kayed Rakez Kayed Tau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes
description	Tau protein is a known contributor in several neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). It is well-established that tau forms pathological aggregates and fibrils in these diseases. Tau has been observed within the nuclei of neurons, but there is a gap in understanding regarding the mechanism by which tau modulates transcription. We are interested in the P301L mutation of tau, which has been associated with FTD and increased tau aggregation. Our study utilized tau-inducible HEK (iHEK) cells to reveal that WT and P301L tau distinctively alter the transcription and alternative polyadenylation (APA) profiles of numerous nuclear precursors mRNAs, which then translate to form proteins involved in chromatin remodeling and splicing. We isolated total mRNA before and after over-expressing tau and then performed Poly(A)-ClickSeq (PAC-Seq) to characterize mRNA expression and APA profiles. We characterized changes in Gene Ontology (GO) pathways using EnrichR and Gene Set Enrichment Analysis (GSEA). We observed that P301L tau up-regulates genes associated with reactive oxygen species responsiveness as well as genes involved in dendrite, microtubule, and nuclear body/speckle formation. The number of genes regulated by WT tau is greater than the mutant form, which indicates that the P301L mutation causes loss-of-function at the transcriptional level. WT tau up-regulates genes contributing to cytoskeleton-dependent intracellular transport, microglial activation, microtubule and nuclear chromatin organization, formation of nuclear bodies and speckles. Interestingly, both WT and P301L tau commonly down-regulate genes responsible for ubiquitin-proteosome system. In addition, WT tau significantly down-regulates several genes implicated in chromatin remodeling and nucleosome organization. Although there are limitations inherent to the model systems used, this study will improve understanding regarding the nuclear impact of tau at the transcriptional and post-transcriptional level. This study also illustrates the potential impact of P301L tau on the human brain genome during early phases of pathogenesis.
format	article
author	Mauro Montalbano Mauro Montalbano Elizabeth Jaworski Stephanie Garcia Stephanie Garcia Anna Ellsworth Anna Ellsworth Salome McAllen Salome McAllen Andrew Routh Andrew Routh Rakez Kayed Rakez Kayed
author_facet	Mauro Montalbano Mauro Montalbano Elizabeth Jaworski Stephanie Garcia Stephanie Garcia Anna Ellsworth Anna Ellsworth Salome McAllen Salome McAllen Andrew Routh Andrew Routh Rakez Kayed Rakez Kayed
author_sort	Mauro Montalbano
title	Tau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes
title_short	Tau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes
title_full	Tau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes
title_fullStr	Tau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes
title_full_unstemmed	Tau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes
title_sort	tau modulates mrna transcription, alternative polyadenylation profiles of hnrnps, chromatin remodeling and spliceosome complexes
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/e82630aa9dc645a094f19b3dcebd97b6
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Tau Modulates mRNA Transcription, Alternative Polyadenylation Profiles of hnRNPs, Chromatin Remodeling and Spliceosome Complexes

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