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Repeat expansion in intron 1 of the Frataxin gene reduces transcription initiation in Friedreich ataxia
Author(s) -
Kumari Daman,
Biacsi Rea Erika,
Usdin Karen
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.895.2
Subject(s) - frataxin , biology , chromatin , genetics , transcription (linguistics) , rna polymerase ii , epigenetics , ataxia , intron , gene , promoter , gene expression , iron binding proteins , neuroscience , linguistics , philosophy
Expansion of a GAA‐repeat tract in the first intron of the frataxin ( FXN ) gene causes an mRNA deficit that results in Friedreich ataxia (FRDA). The region flanking the repeat on FRDA alleles is more extensively methylated than normal alleles and is enriched for repressive histone modifications. However, whether these epigenetic changes are responsible for the mRNA deficit is controversial. We show here that certain marks of active chromatin are also reduced in the promoter region of the FXN gene in patient cells. Thus, the promoter chromatin may be less permissive for transcription initiation than it is on normal alleles. Furthermore, we show that the initiating form of RNA polymerase II and histone H3 trimethylated on lysine 4, a chromatin mark tightly linked to transcription initiation, are both present at lower levels on FRDA alleles. Our data thus supports the idea that repeat‐induced chromatin modifications reduce transcription initiation in FRDA. Our findings may have implications both for understanding the mechanism responsible for FRDA as well as for therapeutic approaches to reverse the transcription deficit.