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

An evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS
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 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.
1932-6203
1-8
Ryu, Hoon
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Savage, Abigail L.
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Wilm, Thomas P.
229453b8-7f3a-429d-81de-8f508e35a353
Khursheed, Kejhal
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Shatunov, Aleksey
e4422e0f-4878-404a-8e9e-fc45b4d5d9bd
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Shaw, Pamela J.
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Shaw, Christopher E.
ad432fe6-4928-445b-a3e1-aaba83c6a530
Smith, Bradley
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Breen, Gerome
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Al-Chalabi, Ammar
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Moss, Diana
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Bubb, Vivien J.
44701ff8-d488-48e9-9809-942b853fa307
Quinn, John P.
f5b6133e-66dc-4cf7-ae02-f6a566b330ed
Ryu, Hoon
8b090580-20d8-484b-b098-ae94a3def8c8
Savage, Abigail L.
55903a37-02c8-4713-9838-7ac943fd856b
Wilm, Thomas P.
229453b8-7f3a-429d-81de-8f508e35a353
Khursheed, Kejhal
5cc44d11-13ed-49b1-93fb-a7fbe3c394c6
Shatunov, Aleksey
e4422e0f-4878-404a-8e9e-fc45b4d5d9bd
Morrison, Karen E.
f00890f0-2fde-4dbd-a73b-7422e1b0ede8
Shaw, Pamela J.
3d0a5c6f-9610-45be-a0bc-5b6888003028
Shaw, Christopher E.
ad432fe6-4928-445b-a3e1-aaba83c6a530
Smith, Bradley
2703005f-a5e9-4a7b-8751-aa5c4d3252d9
Breen, Gerome
6d9e750c-39a7-43ca-9641-320981f38389
Al-Chalabi, Ammar
db16bbda-7684-49b4-9b2d-9799c7dba33c
Moss, Diana
f35a5923-ba9a-46d0-98e9-88762539b5f7
Bubb, Vivien J.
44701ff8-d488-48e9-9809-942b853fa307
Quinn, John P.
f5b6133e-66dc-4cf7-ae02-f6a566b330ed

Ryu, Hoon, Savage, Abigail L., Wilm, Thomas P., Khursheed, Kejhal, Shatunov, Aleksey, Morrison, Karen E., Shaw, Pamela J., Shaw, Christopher E., Smith, Bradley, Breen, Gerome, Al-Chalabi, Ammar, Moss, Diana, Bubb, Vivien J. and Quinn, John P. (2014) An evaluation of a SVA retrotransposon in the FUS promoter as a transcriptional regulator and its association to ALS. PLoS ONE, 9 (3), 1-8. (doi:10.1371/journal.pone.0090833). (PMID:24608899)

Record type: Article

Abstract

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.

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Accepted/In Press date: 2 February 2014
Published date: 7 March 2014
Organisations: Medical Education

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Local EPrints ID: 398323
URI: http://eprints.soton.ac.uk/id/eprint/398323
ISSN: 1932-6203
PURE UUID: 531c5e52-017a-4e7b-a427-80bc3dbe1a5d
ORCID for Karen E. Morrison: ORCID iD orcid.org/0000-0003-0216-5717

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Date deposited: 21 Jul 2016 13:36
Last modified: 17 Dec 2019 01:32

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Contributors

Author: Hoon Ryu
Author: Abigail L. Savage
Author: Thomas P. Wilm
Author: Kejhal Khursheed
Author: Aleksey Shatunov
Author: Pamela J. Shaw
Author: Christopher E. Shaw
Author: Bradley Smith
Author: Gerome Breen
Author: Ammar Al-Chalabi
Author: Diana Moss
Author: Vivien J. Bubb
Author: John P. Quinn

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