Comprehensive analysis of the transcriptional landscape of the human FMR1 gene reveals two new long noncoding RNAs differentially expressed in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome.
Comprehensive analysis of the transcriptional landscape of the human FMR1 gene reveals two new long noncoding RNAs differentially expressed in Fragile X syndrome and Fragile X-associated tremor/ataxia syndrome.
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DOI：
10.1007/s00439-013-1356-6
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发表时间：
2014-01
期刊：
影响因子：
5.3
通讯作者：
Wahlestedt, Claes
中科院分区：
文献类型：
--
作者：
Pastori, Chiara;Peschansky, Veronica J.;Barbouth, Deborah;Mehta, Arpit;Silva, Jose P.;Wahlestedt, Claes
人类基因组的大部分被转录但不翻译，产生非编码RNA（ncRNA），包括在基因调控中执行广泛功能的长ncRNA（lncRNA，>200 nt）。脆性X染色体智力低下1（FMR 1）基因是一个微卫星位点，在一般人群中其5′-非翻译区含有<55个CGG重复。该重复区域扩展到55-200个CGG重复的大小，称为前突变，与脆性X震颤和共济失调综合征（FXTAS）相关。进一步扩增超过200个CGG重复或完全突变，导致FMR 1基因沉默并导致脆性X综合征（FXS）。使用一种称为“Deep-RACE”的新技术，该技术将cDNA末端的快速扩增（RACE）与下一代测序相结合，我们系统地询问了FMR 1基因位点，以寻找新的lncRNA。我们发现了两个转录本，FMR 5和FMR 6。FMR 5是在FMR 1启动子上游转录的正义lncRNA，而FMR 6是与FMR 1的3′区域重叠的反义转录物。FMR 5在未受影响的个体和完全突变和前突变患者的几个人脑区域中表达。FMR 6在完全突变中沉默，并且出乎意料地，在突变前携带者中沉默，表明在过渡到完全突变之前异常转录和/或染色质重塑。因此，这些lncRNA可用作生物标志物，允许FXS和FXTAS的早期检测和治疗干预。最后，我们表明FMR 5和FMR 6在外周血白细胞中表达，并提出了未来的研究，lncRNA表达与临床结果的相关性。本文的在线版本（doi：10.1007/s 00439 -013-1356-6）包含补充材料，可供授权用户使用。
The majority of the human genome is transcribed but not translated, giving rise to noncoding RNAs (ncRNAs), including long ncRNAs (lncRNAs, >200 nt) that perform a wide range of functions in gene regulation. The Fragile X mental retardation 1 (FMR1) gene is a microsatellite locus that in the general population contains <55 CGG repeats in its 5′-untranslated region. Expansion of this repeat region to a size of 55-200 CGG repeats, known as premutation, is associated with Fragile X tremor and ataxia syndrome (FXTAS). Further expansion beyond 200 CGG repeats, or full mutation, leads to FMR1 gene silencing and results in Fragile X syndrome (FXS). Using a novel technology called “Deep-RACE”, which combines rapid amplification of cDNA ends (RACE) with next generation sequencing, we systematically interrogated the FMR1 gene locus for the occurrence of novel lncRNAs. We discovered two transcripts, FMR5 and FMR6. FMR5 is a sense lncRNA transcribed upstream of the FMR1 promoter, whereas FMR6 is an antisense transcript overlapping the 3′ region of FMR1. FMR5 was expressed in several human brain regions from unaffected individuals and from full and premutation patients. FMR6 was silenced in full mutation and, unexpectedly, in premutation carriers suggesting abnormal transcription and/or chromatin remodeling prior to transition to the full mutation. These lncRNAs may thus be useful as biomarkers, allowing for early detection and therapeutic intervention in FXS and FXTAS. Finally we show that FMR5 and FMR6 are expressed in peripheral blood leukocytes and propose future studies that correlate lncRNA expression with clinical outcomes. The online version of this article (doi:10.1007/s00439-013-1356-6) contains supplementary material, which is available to authorized users.
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
16.2
作者：
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DOI：
10.1073/pnas.0605343103
发表时间：
2006-08-15
影响因子：
11.1
作者：
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影响因子：
14.9
作者：
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影响因子：
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通讯作者：
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