Cell-type-specific long-range looping interactions identify distant regulatory elements of the CFTR gene.
Cell-type-specific long-range looping interactions identify distant regulatory elements of the CFTR gene.
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DOI：
10.1093/nar/gkq175
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发表时间：
2010-07
影响因子：
14.9
通讯作者：
Dekker J
中科院分区：
文献类型：
--
作者：
Gheldof N;Smith EM;Tabuchi TM;Koch CM;Dunham I;Stamatoyannopoulos JA;Dekker J
由于调控元件可以在较大的基因组距离上发挥作用，因此调控元件及其靶基因的鉴定变得复杂。长程作用元件的鉴定对于疾病基因尤为重要，因为这些元件的突变可能导致人类疾病。越来越清楚的是，染色质环相互作用促进了基因表达的远程控制。这些相互作用可以通过染色体构象捕获 (3C) 来检测。在这里，我们采用 3C 作为发现工具来识别控制囊性纤维化跨膜电导调节基因 CFTR 的远程调节元件。我们在该基因座周围的 460 kb 区域中鉴定了四个元件，这些元件在 CFTR 表达细胞中专门与 CFTR 启动子特异性循环。这些元素位于上游 20 和 80 kb； CFTR启动子下游109和203 kb。这些元件包含 DNase I 超敏感位点和增强子特有的组蛋白修饰模式。这些元件也会相互作用，后两者在报告基因检测中协同激活 CFTR 启动子。我们的结果揭示了控制 CFTR 表达的新型远程作用元件，并表明基于 3C 的方法可用于发现新型调控元件。
Identification of regulatory elements and their target genes is complicated by the fact that regulatory elements can act over large genomic distances. Identification of long-range acting elements is particularly important in the case of disease genes as mutations in these elements can result in human disease. It is becoming increasingly clear that long-range control of gene expression is facilitated by chromatin looping interactions. These interactions can be detected by chromosome conformation capture (3C). Here, we employed 3C as a discovery tool for identification of long-range regulatory elements that control the cystic fibrosis transmembrane conductance regulator gene, CFTR. We identified four elements in a 460-kb region around the locus that loop specifically to the CFTR promoter exclusively in CFTR expressing cells. The elements are located 20 and 80 kb upstream; and 109 and 203 kb downstream of the CFTR promoter. These elements contain DNase I hypersensitive sites and histone modification patterns characteristic of enhancers. The elements also interact with each other and the latter two activate the CFTR promoter synergistically in reporter assays. Our results reveal novel long-range acting elements that control expression of CFTR and suggest that 3C-based approaches can be used for discovery of novel regulatory elements.
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影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
DOI：
10.1073/pnas.0605343103
发表时间：
2006-08-15
影响因子：
11.1
作者：
Gheldof, Nele;Tabuchi, Tornoko M.;Dekker, Job
通讯作者：
Dekker, Job
影响因子：
4.1
作者：
Blackledge, Neil P.;Carter, Emma J.;Harris, Ann
通讯作者：
Harris, Ann
DOI：
10.1073/pnas.92.16.7560
发表时间：
1995-08-01
影响因子：
11.1
作者：
MCDONALD, RA;MATTHEWS, RP;MCKNIGHT, GS
通讯作者：
MCKNIGHT, GS
影响因子：
12.3
作者：
Dekker J
通讯作者：
Dekker J