共 54 条
The Friedreich ataxia GAA repeat expansion mutation induces comparable epigenetic changes in human and transgenic mouse brain and heart tissues
被引:194
作者:

Al-Mahdawi, Sahar
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机构:
Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England
Brunel Univ, Brunel Inst Canc Genet & Pharmacogenom, Div Biosci, Sch Hlth Sci & Social Care, Uxbridge UB8 3PH, Middx, England Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England

Pinto, Ricardo Mouro
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机构:
Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England
Brunel Univ, Brunel Inst Canc Genet & Pharmacogenom, Div Biosci, Sch Hlth Sci & Social Care, Uxbridge UB8 3PH, Middx, England Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England

Ismail, Ozama
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机构:
Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England
Brunel Univ, Brunel Inst Canc Genet & Pharmacogenom, Div Biosci, Sch Hlth Sci & Social Care, Uxbridge UB8 3PH, Middx, England Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England

Varshney, Dhaval
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机构:
Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England
Brunel Univ, Brunel Inst Canc Genet & Pharmacogenom, Div Biosci, Sch Hlth Sci & Social Care, Uxbridge UB8 3PH, Middx, England Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England

Lymperi, Stefania
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机构:
Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England
Brunel Univ, Brunel Inst Canc Genet & Pharmacogenom, Div Biosci, Sch Hlth Sci & Social Care, Uxbridge UB8 3PH, Middx, England Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England

Sandi, Chiranjeevi
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机构:
Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England
Brunel Univ, Brunel Inst Canc Genet & Pharmacogenom, Div Biosci, Sch Hlth Sci & Social Care, Uxbridge UB8 3PH, Middx, England Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England

Trabzuni, Daniah
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机构:
Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England
Brunel Univ, Brunel Inst Canc Genet & Pharmacogenom, Div Biosci, Sch Hlth Sci & Social Care, Uxbridge UB8 3PH, Middx, England Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England

Pook, Mark
论文数: 0 引用数: 0
h-index: 0
机构:
Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England
Brunel Univ, Brunel Inst Canc Genet & Pharmacogenom, Div Biosci, Sch Hlth Sci & Social Care, Uxbridge UB8 3PH, Middx, England Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England
机构:
[1] Brunel Univ, Hereditary Ataxia Grp, Ctr Cell & Chromosome Biol, Uxbridge UB8 3PH, Middx, England
[2] Brunel Univ, Brunel Inst Canc Genet & Pharmacogenom, Div Biosci, Sch Hlth Sci & Social Care, Uxbridge UB8 3PH, Middx, England
关键词:
D O I:
10.1093/hmg/ddm346
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Friedreich ataxia (FRDA) is caused by a homozygous GAA repeat expansion mutation within intron 1 of the FXN gene, leading to reduced expression of frataxin protein. Evidence suggests that the mutation may induce epigenetic changes and heterochromatin formation, thereby impeding gene transcription. In particular, studies using FRDA patient blood and lymphoblastoid cell lines have detected increased DNA methylation of specific CpG sites upstream of the GAA repeat and histone modifications in regions flanking the GAA repeat. In this report we show that such epigenetic changes are also present in FRDA patient brain, cerebellum and heart tissues, the primary affected systems of the disorder. Bisulfite sequence analysis of the FXN flanking GAA regions reveals a shift in the FRDA DNA methylation profile, with upstream CpG sites becoming consistently hypermethylated and downstream CpG sites becoming consistently hypomethylated. We also identify differential DNA methylation at three specific CpG sites within the FXN promoter and one CpG site within exon 1. Furthermore, we show by chromatin immunoprecipitation analysis that there is overall decreased histone H3K9 acetylation together with increased H3K9 methylation of FRDA brain tissue. Further studies of brain, cerebellum and heart tissues from our GAA repeat expansion-containing FRDA YAC transgenic mice reveal comparable epigenetic changes to those detected in FRDA patient tissue. We have thus developed a mouse model that will be a valuable resource for future therapeutic studies targeting epigenetic modifications of the FXN gene to increase frataxin expression.
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页码:735 / 746
页数:12
相关论文
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Brunel Univ, Sch Hlth Sci & Social Care, Uxbridge UB8 3PH, Middx, England Brunel Univ, Sch Hlth Sci & Social Care, Uxbridge UB8 3PH, Middx, England
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