Characterization of the human TARDBP gene promoter

Abstract The expression of TDP-43, the main component of neuronal intracellular inclusions across a broad spectrum of ALS and FTD disorders, is developmentally regulated and studies in vivo have shown that TDP-43 overexpression can be toxic, even before observation of pathological aggregates. Starti...

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Autores principales:	Marco Baralle, Maurizio Romano
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/289db9c6597a4a4c99f0b853a8df1272
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spelling	oai:doaj.org-article:289db9c6597a4a4c99f0b853a8df12722021-12-02T16:51:04ZCharacterization of the human TARDBP gene promoter10.1038/s41598-021-89973-z2045-2322https://doaj.org/article/289db9c6597a4a4c99f0b853a8df12722021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89973-zhttps://doaj.org/toc/2045-2322Abstract The expression of TDP-43, the main component of neuronal intracellular inclusions across a broad spectrum of ALS and FTD disorders, is developmentally regulated and studies in vivo have shown that TDP-43 overexpression can be toxic, even before observation of pathological aggregates. Starting from these observations, the regulation of its expression at transcriptional level might represent a further key element for the pathogenesis of neurodegenerative diseases. Therefore, we have characterized the human TARDBP promoter, in order to study the transcriptional mechanisms of expression. Mapping of cis-acting elements by luciferase assays in different cell outlined that the activity of the promoter seems to be higher in SH-SY5Y, Neuro2A, and HeLa than in HEK293. In addition, we tested effects of two SNPs found in the promoter region of ALS patients and observed no significant effect on transcription levels in all tested cell lines. Lastly, while TDP-43 overexpression did not affect significantly the activity of its promoter (suggesting that TDP-43 does not influence its own transcription), the presence of the 5′UTR sequence and of intron-1 splicing seem to impact positively on TDP-43 expression without affecting transcript stability. In conclusion, we have identified the region spanning nucleotides 451–230 upstream from the transcription start site as the minimal region with a significant transcription activity. These results lay an important foundation for exploring the regulation of the TARDBP gene transcription by exogenous and endogenous stimuli and the implication of transcriptional mechanisms in the pathogenesis of TDP-43 proteinopathies.Marco BaralleMaurizio RomanoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marco Baralle Maurizio Romano Characterization of the human TARDBP gene promoter
description	Abstract The expression of TDP-43, the main component of neuronal intracellular inclusions across a broad spectrum of ALS and FTD disorders, is developmentally regulated and studies in vivo have shown that TDP-43 overexpression can be toxic, even before observation of pathological aggregates. Starting from these observations, the regulation of its expression at transcriptional level might represent a further key element for the pathogenesis of neurodegenerative diseases. Therefore, we have characterized the human TARDBP promoter, in order to study the transcriptional mechanisms of expression. Mapping of cis-acting elements by luciferase assays in different cell outlined that the activity of the promoter seems to be higher in SH-SY5Y, Neuro2A, and HeLa than in HEK293. In addition, we tested effects of two SNPs found in the promoter region of ALS patients and observed no significant effect on transcription levels in all tested cell lines. Lastly, while TDP-43 overexpression did not affect significantly the activity of its promoter (suggesting that TDP-43 does not influence its own transcription), the presence of the 5′UTR sequence and of intron-1 splicing seem to impact positively on TDP-43 expression without affecting transcript stability. In conclusion, we have identified the region spanning nucleotides 451–230 upstream from the transcription start site as the minimal region with a significant transcription activity. These results lay an important foundation for exploring the regulation of the TARDBP gene transcription by exogenous and endogenous stimuli and the implication of transcriptional mechanisms in the pathogenesis of TDP-43 proteinopathies.
format	article
author	Marco Baralle Maurizio Romano
author_facet	Marco Baralle Maurizio Romano
author_sort	Marco Baralle
title	Characterization of the human TARDBP gene promoter
title_short	Characterization of the human TARDBP gene promoter
title_full	Characterization of the human TARDBP gene promoter
title_fullStr	Characterization of the human TARDBP gene promoter
title_full_unstemmed	Characterization of the human TARDBP gene promoter
title_sort	characterization of the human tardbp gene promoter
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/289db9c6597a4a4c99f0b853a8df1272
work_keys_str_mv	AT marcobaralle characterizationofthehumantardbpgenepromoter AT maurizioromano characterizationofthehumantardbpgenepromoter
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Characterization of the human TARDBP gene promoter

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