Fragile X (CGG)n repeats induce a transcriptional repression in cis upon a linked promoter: evidence for a chromatin mediated effect.
Fragile X (CGG)n repeats induce a transcriptional repression in cis upon a linked promoter: evidence for a chromatin mediated effect.
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脆弱的X（CGG）N重复在连接的启动子上诱导CIS中的转录抑制：染色质介导的作用的证据。
DOI：
10.1186/1471-2199-4-3
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发表时间：
2003-03-21
影响因子：
--
通讯作者：
Hirst, MC
中科院分区：
文献类型：
--
作者：
Chandler, SP;Kansagra, P;Hirst, MC
人FMR1基因启动子区不稳定（CGG）n重复序列扩增至200个以上三联体，导致广泛的局部甲基化和转录沉默，导致FMRP蛋白丢失，并发展为脆性X综合征的临床特征。（CGG）n扩增，甲基化和基因沉默之间的因果关系是未知的，尽管基因沉默与局部染色质结构的广泛变化有关。为了确定在染色质的背景下，基因转录的直接影响的重复长度增加，我们已经研究了从HSV胸苷激酶启动子在非洲爪蟾卵母细胞的转录FMR 1（CGG）n重复的影响。我们观察到mRNA产量的减少与重复长度的增加直接相关，长度超过100个重复的阵列的mRNA产量减少了90%。使用动力学的方法，我们表明，这种转录抑制是伴随着染色质成熟，并在体外转录，我们表明，染色质的形成是一个基本部分的抑制途径介导的（CGG）n重复。使用曲古抑菌素A，组蛋白去乙酰化酶抑制剂，我们显示沉默的启动子的重新激活。因此，分离的脆性X相关（CGG）n重复序列阵列可以对相邻的启动子施加修饰和转录抑制的影响，这种抑制现象部分是由组蛋白去乙酰化介导的。
Expansion of an unstable (CGG)n repeat to over 200 triplets within the promoter region of the human FMR1 gene leads to extensive local methylation and transcription silencing, resulting in the loss of FMRP protein and the development of the clinical features of fragile X syndrome. The causative link between (CGG)n expansion, methylation and gene silencing is unknown, although gene silencing is associated with extensive changes to local chromatin architecture. In order to determine the direct effects of increased repeat length on gene transcription in a chromatin context, we have examined the influence of FMR1 (CGG)n repeats upon transcription from the HSV thymidine kinase promoter in the Xenopus laevis oocyte. We observe a reduction in mRNA production directly associated with increasing repeat length, with a 90% reduction in mRNA production from arrays over 100 repeats in length. Using a kinetic approach, we show that this transcriptional repression is concomitant with chromatin maturation and, using in vitro transcription, we show that chromatin formation is a fundamental part of the repressive pathway mediated by (CGG)n repeats. Using Trichostatin A, a histone deacetylase inhibitor, we show reactivation of the silenced promoter. Thus, isolated fragile X associated (CGG)n repeat arrays can exert a modifying and transcriptionally repressive influence over adjacent promoters and this repressive phenomenon is, in part, mediated by histone deacetylation.
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DOI：
10.1073/pnas.92.11.5199
发表时间：
1995-05-23
影响因子：
11.1
作者：
CHEN, XA;MARIAPPAN, SVS;GUPTA, G
通讯作者：
GUPTA, G
影响因子：
11.4
作者：
Gregory, PD;Schmid, A;Hörz, W
通讯作者：
Hörz, W
影响因子：
2.9
作者：
Chandler, SP;Guschin, D;Wolffe, AP
通讯作者：
Wolffe, AP
影响因子：
4.8
作者：
Deissler, H;Wilm, M;Doerfler, W
通讯作者：
Doerfler, W
影响因子：
14.9
作者：
Hirst, MC;White, PJ
通讯作者：
White, PJ