Epigenetic Silencing in Friedreich Ataxia Is Associated with Depletion of CTCF (CCCTC-Binding Factor) and Antisense Transcription
Epigenetic Silencing in Friedreich Ataxia Is Associated with Depletion of CTCF (CCCTC-Binding Factor) and Antisense Transcription
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DOI：
10.1371/journal.pone.0007914
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发表时间：
2009-11-19
期刊：
影响因子：
3.7
通讯作者：
Bidichandani, Sanjay I.
中科院分区：
文献类型：
--
作者：
De Biase, Irene;Chutake, Yogesh K.;Bidichandani, Sanjay I.
背景：超过15种遗传性疾病是由三重重复序列扩增引起的。弗里德赖希共济失调（FRDA）患者是FXN基因内含子1中扩展的GAA三联体重复序列纯合子。扩展的GAA三重重复序列导致FXN基因转录的缺陷，其通过给予组蛋白脱乙酰酶抑制剂而逆转，表明转录沉默至少部分是由于表观遗传异常。我们发现了一个严重的染色质绝缘子蛋白CTCF损耗FRDA中FXN基因的5 'UTR中的CCCTC结合因子（CCCTC结合因子），以及通过H3 K9 me 3的富集和异染色质蛋白1的募集涉及+1核小体的同时异染色质形成。我们鉴定了FAST-1（FXN反义转录物-1），这是一种与5 'UTR中的CTCF结合位点重叠的新型反义转录物，其在FRDA中以更高水平表达。在正常细胞中，通过敲低CTCF.Conclusions/Significance：CTCF耗竭构成了一个表观遗传开关，导致FRDA中反义转录增加、异染色质形成和转录缺陷，从而复制了FRDA中FXN转录缺陷和FAST-1水平较高的相互关系。这些发现为FRDA中FXN基因的转录沉默提供了机制基础，并拓宽了我们对三联体重复疾病发病机制的理解。
Background: Over 15 inherited diseases are caused by expansion of triplet-repeats. Friedreich ataxia (FRDA) patients are homozygous for an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene. The expanded GAA triplet-repeat results in deficiency of FXN gene transcription, which is reversed via administration of histone deacetylase inhibitors indicating that transcriptional silencing is at least partially due to an epigenetic abnormality.Methodology/Principal Findings: We found a severe depletion of the chromatin insulator protein CTCF (CCCTC-binding factor) in the 5'UTR of the FXN gene in FRDA, and coincident heterochromatin formation involving the +1 nucleosome via enrichment of H3K9me3 and recruitment of heterochromatin protein 1. We identified FAST-1 (FXN Antisense Transcript - 1), a novel antisense transcript that overlaps the CTCF binding site in the 5'UTR, which was expressed at higher levels in FRDA. The reciprocal relationship of deficient FXN transcript and higher levels of FAST-1 seen in FRDA was reproduced in normal cells via knockdown of CTCF.Conclusions/Significance: CTCF depletion constitutes an epigenetic switch that results in increased antisense transcription, heterochromatin formation and transcriptional deficiency in FRDA. These findings provide a mechanistic basis for the transcriptional silencing of the FXN gene in FRDA, and broaden our understanding of disease pathogenesis in triplet-repeat diseases.