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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/36529
Acceder
id CONICETDig_8e39530f22ca38ca5808e1565ecb8b32
oai_identifier_str oai:ri.conicet.gov.ar:11336/36529
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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 Técnicas2025-10-22T12:00:08Zoai: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:34982025-10-22 12:00:08.858CONICET 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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score 13.129756

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