Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia.
Repeat-induced epigenetic changes in intron 1 of the frataxin gene and its consequences in Friedreich ataxia.
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DOI：
10.1093/nar/gkm271
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发表时间：
2007
影响因子：
14.9
通讯作者：
Usdin K
中科院分区：
文献类型：
--
作者：
Greene E;Mahishi L;Entezam A;Kumari D;Usdin K
Friedreich共济失调(FRDA)是最常见的遗传性共济失调，由Frataxin(FXN)基因突变引起。绝大多数FRDA突变涉及内含子1中GAA·TTC-重复序列的扩张，导致FXN mRNA缺失。亚硫酸氢盐图谱显示，在未受影响的个体和受影响的个体中，重复序列附近的区域都发生了甲基化。然而，甲基化在患者中更为广泛。此外，在未受影响的个体中，三个残基几乎完全没有甲基化，但在有FRDA的个体中几乎总是甲基化。其中一个残基位于E-box内，其缺失会导致报告分析中启动子活性的显著下降。在FRDA细胞中，赖氨酸9上二甲基化的组蛋白H3水平升高，这与更具抑制性的染色质组织相一致。已知这种染色质会降低转录伸长。这可能是扩大的重复序列导致FRDA中Frataxin缺陷的一种方式。我们的数据还表明，重复介导的染色质变化也可能通过阻断增加Frataxin启动子活性的因子的结合来影响转录启动。我们的结果也提出了一种可能性，即FRDA患者FXN基因中重复介导的DNA甲基化增加是次要于染色质变化的。
Friedreich ataxia (FRDA), the most common hereditary ataxia, is caused by mutations in the frataxin (FXN) gene. The vast majority of FRDA mutations involve expansion of a GAA•TTC-repeat tract in intron 1, which leads to an FXN mRNA deficit. Bisulfite mapping demonstrates that the region adjacent to the repeat was methylated in both unaffected and affected individuals. However, methylation was more extensive in patients. Additionally, three residues were almost completely methylation-free in unaffected individuals but almost always methylated in those with FRDA. One of these residues is located within an E-box whose deletion caused a significant drop in promoter activity in reporter assays. Elevated levels of histone H3 dimethylated on lysine 9 were seen in FRDA cells consistent with a more repressive chromatin organization. Such chromatin is known to reduce transcription elongation. This may be one way in which the expanded repeats contribute to the frataxin deficit in FRDA. Our data also suggest that repeat-mediated chromatin changes may also affect transcription initiation by blocking binding of factors that increase frataxin promoter activity. Our results also raise the possibility that the repeat-mediated increases in DNA methylation in the FXN gene in FRDA patients are secondary to the chromatin changes.
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影响因子：
56.9
作者：
Volpe, TA;Kidner, C;Martienssen, RA
通讯作者：
Martienssen, RA
影响因子：
16.8
作者：
Lorincz, MC;Dickerson, DR;Groudine, M
通讯作者：
Groudine, M
DOI：
10.1073/pnas.0508085102
发表时间：
2005-11-08
影响因子：
11.1
作者：
Lee, JG;Dahi, S;Sarkar, R
通讯作者：
Sarkar, R
影响因子：
11.4
作者：
Martens, JHA;O'Sullivan, RJ;Jenuwein, T
通讯作者：
Jenuwein, T
影响因子：
14.9
作者：
CORPET, F
通讯作者：
CORPET, F