Repeat Expansion Affects Both Transcription Initiation and Elongation in Friedreich Ataxia Cells
Repeat Expansion Affects Both Transcription Initiation and Elongation in Friedreich Ataxia Cells
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DOI：
10.1074/jbc.m110.194035
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发表时间：
2011-02-01
影响因子：
4.8
通讯作者：
Usdin, Karen
中科院分区：
文献类型：
--
作者：
Kumari, Daman;Biacsi, Rea Erika;Usdin, Karen
Frataxin(FXN)基因第一内含子中GAA.TTC重复序列的扩展会导致mRNA缺陷，从而导致Friedreich共济失调(FRDA)。与正常等位基因和组蛋白修饰相比，FRDA等位基因重复序列两侧的区域与更广泛的DNA甲基化有关。然而，这些变化是否导致了信使核糖核酸的缺失仍存在争议。利用染色质免疫沉淀和来自患者和未受影响个体的细胞系，我们发现患者细胞中FXN基因启动子区域的某些活性染色质标记也减少了。因此，与正常等位基因相比，启动子染色质对转录启动的容许性可能较低。此外，我们还发现，在与转录起始密切相关的染色质标记赖氨酸4上，RNA聚合酶II和组蛋白H3的起始型都存在于FRDA等位基因的较低水平。此外，转录延长的标志，三甲基化的H3K36，显示重复序列下游积累的速度降低。因此，我们的数据表明，重复扩增降低了FRDA细胞的转录起始和延伸。我们的发现可能对理解FRDA的机制以及逆转转录缺陷的治疗方法有意义。
Expansion of a GAA.TTC repeat 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 associated with more extensive DNA methylation than is seen on normal alleles and histone modifications typical of repressed genes. However, whether these changes are responsible for the mRNA deficit is controversial. Using chromatin immunoprecipitation and cell lines from affected and unaffected individuals, we show 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. In addition, a mark of transcription elongation, trimethylated H3K36, shows a reduced rate of accumulation downstream of the repeat. Our data thus suggest that repeat expansion reduces both transcription initiation and elongation in FRDA cells. Our findings may have implications for understanding the mechanism responsible for FRDA as well as for therapeutic approaches to reverse the transcription deficit.