An evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS.

Genetic mutations of FUS have been linked to many diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration. A primate specific and polymorphic retrotransposon of the SINE-VNTR-Alu (SVA) family is present upstream of the FUS gene. Here we have demonstrated that thi...

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Autores principales:	Abigail L Savage, Thomas P Wilm, Kejhal Khursheed, Aleksey Shatunov, Karen E Morrison, Pamela J Shaw, Christopher E Shaw, Bradley Smith, Gerome Breen, Ammar Al-Chalabi, Diana Moss, Vivien J Bubb, John P Quinn
Formato:	article
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Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/042fd4e948994b3b8766b4695db23620
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spelling	oai:doaj.org-article:042fd4e948994b3b8766b4695db236202021-11-18T08:29:08ZAn evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS.1932-620310.1371/journal.pone.0090833https://doaj.org/article/042fd4e948994b3b8766b4695db236202014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24608899/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Genetic mutations of FUS have been linked to many diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration. A primate specific and polymorphic retrotransposon of the SINE-VNTR-Alu (SVA) family is present upstream of the FUS gene. Here we have demonstrated that this retrotransposon can act as a classical transcriptional regulatory domain in the context of a reporter gene construct both in vitro in the human SK-N-AS neuroblastoma cell line and in vivo in a chick embryo model. We have also demonstrated that the SVA is composed of multiple distinct regulatory domains, one of which is a variable number tandem repeat (VNTR). The ability of the SVA and its component parts to direct reporter gene expression supported a hypothesis that this region could direct differential FUS expression in vivo. The SVA may therefore contribute to the modulation of FUS expression exhibited in and associated with neurological disorders including ALS where FUS regulation may be an important parameter in progression of the disease. As VNTRs are often clinical associates for disease progression we determined the extent of polymorphism within the SVA. In total 2 variants of the SVA were identified based within a central VNTR. Preliminary analysis addressed the association of these SVA variants within a small sporadic ALS cohort but did not reach statistical significance, although we did not include other parameters such as SNPs within the SVA or an environmental factor in this analysis. The latter may be particularly important as the transcriptional and epigenetic properties of the SVA are likely to be directed by the environment of the cell.Abigail L SavageThomas P WilmKejhal KhursheedAleksey ShatunovKaren E MorrisonPamela J ShawChristopher E ShawBradley SmithGerome BreenAmmar Al-ChalabiDiana MossVivien J BubbJohn P QuinnPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 6, p e90833 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Abigail L Savage Thomas P Wilm Kejhal Khursheed Aleksey Shatunov Karen E Morrison Pamela J Shaw Christopher E Shaw Bradley Smith Gerome Breen Ammar Al-Chalabi Diana Moss Vivien J Bubb John P Quinn An evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS.
description	Genetic mutations of FUS have been linked to many diseases including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration. A primate specific and polymorphic retrotransposon of the SINE-VNTR-Alu (SVA) family is present upstream of the FUS gene. Here we have demonstrated that this retrotransposon can act as a classical transcriptional regulatory domain in the context of a reporter gene construct both in vitro in the human SK-N-AS neuroblastoma cell line and in vivo in a chick embryo model. We have also demonstrated that the SVA is composed of multiple distinct regulatory domains, one of which is a variable number tandem repeat (VNTR). The ability of the SVA and its component parts to direct reporter gene expression supported a hypothesis that this region could direct differential FUS expression in vivo. The SVA may therefore contribute to the modulation of FUS expression exhibited in and associated with neurological disorders including ALS where FUS regulation may be an important parameter in progression of the disease. As VNTRs are often clinical associates for disease progression we determined the extent of polymorphism within the SVA. In total 2 variants of the SVA were identified based within a central VNTR. Preliminary analysis addressed the association of these SVA variants within a small sporadic ALS cohort but did not reach statistical significance, although we did not include other parameters such as SNPs within the SVA or an environmental factor in this analysis. The latter may be particularly important as the transcriptional and epigenetic properties of the SVA are likely to be directed by the environment of the cell.
format	article
author	Abigail L Savage Thomas P Wilm Kejhal Khursheed Aleksey Shatunov Karen E Morrison Pamela J Shaw Christopher E Shaw Bradley Smith Gerome Breen Ammar Al-Chalabi Diana Moss Vivien J Bubb John P Quinn
author_facet	Abigail L Savage Thomas P Wilm Kejhal Khursheed Aleksey Shatunov Karen E Morrison Pamela J Shaw Christopher E Shaw Bradley Smith Gerome Breen Ammar Al-Chalabi Diana Moss Vivien J Bubb John P Quinn
author_sort	Abigail L Savage
title	An evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS.
title_short	An evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS.
title_full	An evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS.
title_fullStr	An evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS.
title_full_unstemmed	An evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS.
title_sort	evaluation of a sva retrotransposon in the fus promoter as a transcriptional regulator and its association to als.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/042fd4e948994b3b8766b4695db23620
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An evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS.

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