Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients
- Autores
- Xi, Zhengrui; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Bruni, Amalia C.; Maletta, Raffaele G.; Nacmias, Benedetta; Sorbi, Sandro; Galimberti, Daniela; Surace, Ezequiel Ignacio; Zheng, Yonglan; Moreno, Danielle; Sato, Christine; Liang, Yan; Zhou, Ye; Robertson, Janice; Zinman, Lorne; Tartaglia, Maria Carmela; St. George Hyslop, Peter; Rogaeva, Ekaterina
- Año de publicación
- 2014
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- The G4C2-repeat expansion in C9orf72 is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 transcription is reduced in expansion carriers implicating haploinsufficiency as one of the disease mechanisms. Indeed, our recent ALS study revealed that the expansion was associated with hypermethylation of theCpG-island (5′of the repeat) inDNAsamples obtained from different tissues (blood, brain and spinal cord). However, the link between FTLD and methylation of the CpG-island is unknown. Hence, we investigated the methylation profile of the same CpG-island by bisulfite sequencing of DNA obtained from blood of 34 FTLD expansion carriers, 166 FTLD non-carriers and 103 controls. Methylation levelwassignificantly higher inFTLDexpansion carriers than non-carriers (P 5 7.8E213). Ourresults were confirmed by two methods (HhaI-assay and sequencing of cloned bisulfite PCR products). Hypermethylation occurred only in carriers of an allele with >50 repeats, and was not detected in non-carriers or individuals with an intermediate allele (22-43 repeats). As expected, the position/number of methylated CpGs was concordant between the sense and anti-sense DNA strand, suggesting that it is a stable epigenetic modification. Analysis of the combined ALS and FTLD datasets (82 expansion carriers) revealed that the degree of methylation of the entire CpG-island or contribution of specific CpGs (n 5 26) is similar in both syndromes, with a trend towards a higher proportion of ALS patients with a high methylation level (P 5 0.09). In conclusion, we demonstrated that hypermethylation of the CpG-island 5′of the G4C2-repeat is expansion-specific, but not syndrome-specific (ALS versus FTLD).
Fil: Xi, Zhengrui. University of Toronto; Canadá
Fil: Rainero, Innocenzo. Università di Torino; Italia
Fil: Rubino, Elisa. Università di Torino; Italia
Fil: Pinessi, Lorenzo. Università di Torino; Italia
Fil: Bruni, Amalia C.. Neurogenetic Research Centre; Italia
Fil: Maletta, Raffaele G.. Neurogenetic Research Centre; Italia
Fil: Nacmias, Benedetta. Universita Degli Studi Di Firenze; Italia
Fil: Sorbi, Sandro. Universita Degli Studi Di Firenze; Italia
Fil: Galimberti, Daniela. Università degli Studi di Milano; Italia
Fil: Surace, Ezequiel Ignacio. Instituto de Investigaciones Neurologicas Raul Carrera; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Zheng, Yonglan. University of Chicago; Estados Unidos
Fil: Moreno, Danielle. University of Toronto; Canadá
Fil: Sato, Christine. University of Toronto; Canadá
Fil: Liang, Yan. University of Toronto; Canadá
Fil: Zhou, Ye. University of Toronto; Canadá
Fil: Robertson, Janice. University of Toronto; Canadá
Fil: Zinman, Lorne. University of Toronto; Canadá. Sunnybrook Health Sciences Centre; Canadá
Fil: Tartaglia, Maria Carmela. University of Toronto; Canadá
Fil: St. George Hyslop, Peter. Cambridge Institute For Medical Research; Reino Unido. University of Toronto; Canadá
Fil: Rogaeva, Ekaterina. University of Toronto; Canadá - Materia
-
Neurodegeneration
Methylation
Epigenetics
Dementia - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/36529
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Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patientsXi, ZhengruiRainero, InnocenzoRubino, ElisaPinessi, LorenzoBruni, Amalia C.Maletta, Raffaele G.Nacmias, BenedettaSorbi, SandroGalimberti, DanielaSurace, Ezequiel IgnacioZheng, YonglanMoreno, DanielleSato, ChristineLiang, YanZhou, YeRobertson, JaniceZinman, LorneTartaglia, Maria CarmelaSt. George Hyslop, PeterRogaeva, EkaterinaNeurodegenerationMethylationEpigeneticsDementiahttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3The G4C2-repeat expansion in C9orf72 is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 transcription is reduced in expansion carriers implicating haploinsufficiency as one of the disease mechanisms. Indeed, our recent ALS study revealed that the expansion was associated with hypermethylation of theCpG-island (5′of the repeat) inDNAsamples obtained from different tissues (blood, brain and spinal cord). However, the link between FTLD and methylation of the CpG-island is unknown. Hence, we investigated the methylation profile of the same CpG-island by bisulfite sequencing of DNA obtained from blood of 34 FTLD expansion carriers, 166 FTLD non-carriers and 103 controls. Methylation levelwassignificantly higher inFTLDexpansion carriers than non-carriers (P 5 7.8E213). Ourresults were confirmed by two methods (HhaI-assay and sequencing of cloned bisulfite PCR products). Hypermethylation occurred only in carriers of an allele with >50 repeats, and was not detected in non-carriers or individuals with an intermediate allele (22-43 repeats). As expected, the position/number of methylated CpGs was concordant between the sense and anti-sense DNA strand, suggesting that it is a stable epigenetic modification. Analysis of the combined ALS and FTLD datasets (82 expansion carriers) revealed that the degree of methylation of the entire CpG-island or contribution of specific CpGs (n 5 26) is similar in both syndromes, with a trend towards a higher proportion of ALS patients with a high methylation level (P 5 0.09). In conclusion, we demonstrated that hypermethylation of the CpG-island 5′of the G4C2-repeat is expansion-specific, but not syndrome-specific (ALS versus FTLD).Fil: Xi, Zhengrui. University of Toronto; CanadáFil: Rainero, Innocenzo. Università di Torino; ItaliaFil: Rubino, Elisa. Università di Torino; ItaliaFil: Pinessi, Lorenzo. Università di Torino; ItaliaFil: Bruni, Amalia C.. Neurogenetic Research Centre; ItaliaFil: Maletta, Raffaele G.. Neurogenetic Research Centre; ItaliaFil: Nacmias, Benedetta. Universita Degli Studi Di Firenze; ItaliaFil: Sorbi, Sandro. Universita Degli Studi Di Firenze; ItaliaFil: Galimberti, Daniela. Università degli Studi di Milano; ItaliaFil: Surace, Ezequiel Ignacio. Instituto de Investigaciones Neurologicas Raul Carrera; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Zheng, Yonglan. University of Chicago; Estados UnidosFil: Moreno, Danielle. University of Toronto; CanadáFil: Sato, Christine. University of Toronto; CanadáFil: Liang, Yan. University of Toronto; CanadáFil: Zhou, Ye. University of Toronto; CanadáFil: Robertson, Janice. University of Toronto; CanadáFil: Zinman, Lorne. University of Toronto; Canadá. Sunnybrook Health Sciences Centre; CanadáFil: Tartaglia, Maria Carmela. University of Toronto; CanadáFil: St. George Hyslop, Peter. Cambridge Institute For Medical Research; Reino Unido. University of Toronto; CanadáFil: Rogaeva, Ekaterina. University of Toronto; CanadáOxford University Press2014-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/36529Xi, Zhengrui; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Bruni, Amalia C.; et al.; Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients; Oxford University Press; Human Molecular Genetics; 23; 21; 11-2014; 5630-56370964-6906CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1093/hmg/ddu279info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/hmg/article/23/21/5630/2901002info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:27:43Zoai:ri.conicet.gov.ar:11336/36529instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:27:43.688CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients |
title |
Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients |
spellingShingle |
Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients Xi, Zhengrui Neurodegeneration Methylation Epigenetics Dementia |
title_short |
Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients |
title_full |
Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients |
title_fullStr |
Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients |
title_full_unstemmed |
Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients |
title_sort |
Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients |
dc.creator.none.fl_str_mv |
Xi, Zhengrui Rainero, Innocenzo Rubino, Elisa Pinessi, Lorenzo Bruni, Amalia C. Maletta, Raffaele G. Nacmias, Benedetta Sorbi, Sandro Galimberti, Daniela Surace, Ezequiel Ignacio Zheng, Yonglan Moreno, Danielle Sato, Christine Liang, Yan Zhou, Ye Robertson, Janice Zinman, Lorne Tartaglia, Maria Carmela St. George Hyslop, Peter Rogaeva, Ekaterina |
author |
Xi, Zhengrui |
author_facet |
Xi, Zhengrui Rainero, Innocenzo Rubino, Elisa Pinessi, Lorenzo Bruni, Amalia C. Maletta, Raffaele G. Nacmias, Benedetta Sorbi, Sandro Galimberti, Daniela Surace, Ezequiel Ignacio Zheng, Yonglan Moreno, Danielle Sato, Christine Liang, Yan Zhou, Ye Robertson, Janice Zinman, Lorne Tartaglia, Maria Carmela St. George Hyslop, Peter Rogaeva, Ekaterina |
author_role |
author |
author2 |
Rainero, Innocenzo Rubino, Elisa Pinessi, Lorenzo Bruni, Amalia C. Maletta, Raffaele G. Nacmias, Benedetta Sorbi, Sandro Galimberti, Daniela Surace, Ezequiel Ignacio Zheng, Yonglan Moreno, Danielle Sato, Christine Liang, Yan Zhou, Ye Robertson, Janice Zinman, Lorne Tartaglia, Maria Carmela St. George Hyslop, Peter Rogaeva, Ekaterina |
author2_role |
author author author author author author author author author author author author author author author author author author author |
dc.subject.none.fl_str_mv |
Neurodegeneration Methylation Epigenetics Dementia |
topic |
Neurodegeneration Methylation Epigenetics Dementia |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
The G4C2-repeat expansion in C9orf72 is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 transcription is reduced in expansion carriers implicating haploinsufficiency as one of the disease mechanisms. Indeed, our recent ALS study revealed that the expansion was associated with hypermethylation of theCpG-island (5′of the repeat) inDNAsamples obtained from different tissues (blood, brain and spinal cord). However, the link between FTLD and methylation of the CpG-island is unknown. Hence, we investigated the methylation profile of the same CpG-island by bisulfite sequencing of DNA obtained from blood of 34 FTLD expansion carriers, 166 FTLD non-carriers and 103 controls. Methylation levelwassignificantly higher inFTLDexpansion carriers than non-carriers (P 5 7.8E213). Ourresults were confirmed by two methods (HhaI-assay and sequencing of cloned bisulfite PCR products). Hypermethylation occurred only in carriers of an allele with >50 repeats, and was not detected in non-carriers or individuals with an intermediate allele (22-43 repeats). As expected, the position/number of methylated CpGs was concordant between the sense and anti-sense DNA strand, suggesting that it is a stable epigenetic modification. Analysis of the combined ALS and FTLD datasets (82 expansion carriers) revealed that the degree of methylation of the entire CpG-island or contribution of specific CpGs (n 5 26) is similar in both syndromes, with a trend towards a higher proportion of ALS patients with a high methylation level (P 5 0.09). In conclusion, we demonstrated that hypermethylation of the CpG-island 5′of the G4C2-repeat is expansion-specific, but not syndrome-specific (ALS versus FTLD). Fil: Xi, Zhengrui. University of Toronto; Canadá Fil: Rainero, Innocenzo. Università di Torino; Italia Fil: Rubino, Elisa. Università di Torino; Italia Fil: Pinessi, Lorenzo. Università di Torino; Italia Fil: Bruni, Amalia C.. Neurogenetic Research Centre; Italia Fil: Maletta, Raffaele G.. Neurogenetic Research Centre; Italia Fil: Nacmias, Benedetta. Universita Degli Studi Di Firenze; Italia Fil: Sorbi, Sandro. Universita Degli Studi Di Firenze; Italia Fil: Galimberti, Daniela. Università degli Studi di Milano; Italia Fil: Surace, Ezequiel Ignacio. Instituto de Investigaciones Neurologicas Raul Carrera; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Zheng, Yonglan. University of Chicago; Estados Unidos Fil: Moreno, Danielle. University of Toronto; Canadá Fil: Sato, Christine. University of Toronto; Canadá Fil: Liang, Yan. University of Toronto; Canadá Fil: Zhou, Ye. University of Toronto; Canadá Fil: Robertson, Janice. University of Toronto; Canadá Fil: Zinman, Lorne. University of Toronto; Canadá. Sunnybrook Health Sciences Centre; Canadá Fil: Tartaglia, Maria Carmela. University of Toronto; Canadá Fil: St. George Hyslop, Peter. Cambridge Institute For Medical Research; Reino Unido. University of Toronto; Canadá Fil: Rogaeva, Ekaterina. University of Toronto; Canadá |
description |
The G4C2-repeat expansion in C9orf72 is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 transcription is reduced in expansion carriers implicating haploinsufficiency as one of the disease mechanisms. Indeed, our recent ALS study revealed that the expansion was associated with hypermethylation of theCpG-island (5′of the repeat) inDNAsamples obtained from different tissues (blood, brain and spinal cord). However, the link between FTLD and methylation of the CpG-island is unknown. Hence, we investigated the methylation profile of the same CpG-island by bisulfite sequencing of DNA obtained from blood of 34 FTLD expansion carriers, 166 FTLD non-carriers and 103 controls. Methylation levelwassignificantly higher inFTLDexpansion carriers than non-carriers (P 5 7.8E213). Ourresults were confirmed by two methods (HhaI-assay and sequencing of cloned bisulfite PCR products). Hypermethylation occurred only in carriers of an allele with >50 repeats, and was not detected in non-carriers or individuals with an intermediate allele (22-43 repeats). As expected, the position/number of methylated CpGs was concordant between the sense and anti-sense DNA strand, suggesting that it is a stable epigenetic modification. Analysis of the combined ALS and FTLD datasets (82 expansion carriers) revealed that the degree of methylation of the entire CpG-island or contribution of specific CpGs (n 5 26) is similar in both syndromes, with a trend towards a higher proportion of ALS patients with a high methylation level (P 5 0.09). In conclusion, we demonstrated that hypermethylation of the CpG-island 5′of the G4C2-repeat is expansion-specific, but not syndrome-specific (ALS versus FTLD). |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014-11 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/36529 Xi, Zhengrui; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Bruni, Amalia C.; et al.; Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients; Oxford University Press; Human Molecular Genetics; 23; 21; 11-2014; 5630-5637 0964-6906 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/36529 |
identifier_str_mv |
Xi, Zhengrui; Rainero, Innocenzo; Rubino, Elisa; Pinessi, Lorenzo; Bruni, Amalia C.; et al.; Hypermethylation of the CpG-island near the C9orf72 G4C2-repeat expansion in FTLD patients; Oxford University Press; Human Molecular Genetics; 23; 21; 11-2014; 5630-5637 0964-6906 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1093/hmg/ddu279 info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/hmg/article/23/21/5630/2901002 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Oxford University Press |
publisher.none.fl_str_mv |
Oxford University Press |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844614279643267072 |
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13.070432 |