Genome-wide detection of a TFIID localization element from an initial human disease mutation.
Genome-wide detection of a TFIID localization element from an initial human disease mutation.
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从初始人类疾病突变中对TFIID定位元件的全基因组检测。
DOI：
10.1093/nar/gkq1035
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发表时间：
2011-03
影响因子：
14.9
通讯作者：
Elnitski L
中科院分区：
文献类型：
--
作者：
Yang MQ;Laflamme K;Gotea V;Joiner CH;Seidel NE;Wong C;Petrykowska HM;Lichtenberg J;Lee S;Welch L;Gallagher PG;Bodine DM;Elnitski L
真核核心启动子的特征通常在于存在共有基序，如TATA盒或起始元件，其吸引并引导转录机器至转录起始位点。然而，许多人类启动子没有已知的核心启动子基序，这表明基因组中存在未发现的启动子基序。我们以前确定了人类锚蛋白-1（ANK-1）启动子的突变，导致疾病锚蛋白缺陷型遗传性球形细胞增多症（HS）。虽然ANK-1启动子富含CpG，但尚未鉴定出可辨别的基础启动子元件。我们发现HS突变破坏了转录因子TFIID的结合，TFIID是前起始复合物的主要成分。我们假设，该突变确定了一个候选启动子元件，在基因调控中具有更广泛的作用。我们研究了17 181人启动子的实验验证的结合位点，称为TFIID定位序列（DLS），发现三倍多的启动子含有DLS比TATA基序。DLS序列的突变分析证实了它们的功能意义，就像在最小的Sp1启动子上添加DLS位点一样。我们的研究结果表明，新的启动子元件可以通过观察导致人类疾病的监管中断在全基因组范围内确定。
Eukaryotic core promoters are often characterized by the presence of consensus motifs such as the TATA box or initiator elements, which attract and direct the transcriptional machinery to the transcription start site. However, many human promoters have none of the known core promoter motifs, suggesting that undiscovered promoter motifs exist in the genome. We previously identified a mutation in the human Ankyrin-1 (ANK-1) promoter that causes the disease ankyrin-deficient Hereditary Spherocytosis (HS). Although the ANK-1 promoter is CpG rich, no discernable basal promoter elements had been identified. We showed that the HS mutation disrupted the binding of the transcription factor TFIID, the major component of the pre-initiation complex. We hypothesized that the mutation identified a candidate promoter element with a more widespread role in gene regulation. We examined 17 181 human promoters for the experimentally validated binding site, called the TFIID localization sequence (DLS) and found three times as many promoters containing DLS than TATA motifs. Mutational analyses of DLS sequences confirmed their functional significance, as did the addition of a DLS site to a minimal Sp1 promoter. Our results demonstrate that novel promoter elements can be identified on a genome-wide scale through observations of regulatory disruptions that cause human disease.
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影响因子：
5.3
作者：
BLAKE, MC;JAMBOU, RC;AZIZKHAN, JC
通讯作者：
AZIZKHAN, JC
影响因子：
2.9
作者：
Li, L;He, SH;Davie, JR
通讯作者：
Davie, JR
影响因子：
10.5
作者：
Emami, KH;Jain, A;Smale, ST
通讯作者：
Smale, ST
影响因子：
3.9
作者：
Juven-Gershon, T.;Hsu, J. -Y.;Kadonaga, J. T.
通讯作者：
Kadonaga, J. T.
影响因子：
7.5
作者：
Juven-Gershon, Tamar;Hsu, Jer-Yuan;Kadonaga, James T.
通讯作者：
Kadonaga, James T.