A genome-wide analysis of open chromatin in human tracheal epithelial cells reveals novel candidate regulatory elements for lung function.
A genome-wide analysis of open chromatin in human tracheal epithelial cells reveals novel candidate regulatory elements for lung function.
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DOI：
10.1136/thoraxjnl-2011-200880
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发表时间：
2012-05
期刊：
影响因子：
10
通讯作者：
Harris A
中科院分区：
文献类型：
--
作者：
Bischof JM;Ott CJ;Leir SH;Gosalia N;Song L;London D;Furey TS;Cotton CU;Crawford GE;Harris A
远端细胞类型特异性调控元件可以位于距它们控制的基因非常大的距离处，并且通常隐藏在基因间区域内或其他基因的内含子中。开发的方法，使开放的染色质基因组范围内的区域映射，大大推进了这些元素的识别和表征。在这里，我们使用DNase I超敏反应作图，然后进行深度测序（DNase-seq），以生成原代人气管上皮（HTE）细胞中开放染色质的图谱，并使用生物信息学方法来确定这些位点在基因组中的分布，以及基因启动子，内含子和基因间区域。在其启动子处具有HTE选择性开放染色质的基因与上皮功能和分化的多种途径相关。这些数据预测了新的细胞类型特异性调控元件，用于参与HTE细胞功能的基因，如结构蛋白和离子通道，以及可能与它们相互作用以控制基因表达的转录因子。此外，开放染色质图谱可以在全基因组关联研究（GWAS）中识别潜在关键调控元件的位置，其中最强的关联是与基因组非编码区的单核苷酸多态性。我们证明了它的相关性，最近的GWAS，确定囊性纤维化肺疾病的严重程度的修饰符。由于HTE细胞与支气管上皮细胞和呼吸道上皮中的其他分化细胞具有许多功能相似性，因此这些数据与阐明正常肺功能和肺部疾病的分子基础直接相关。
Distal cell-type-specific regulatory elements may be located at very large distances from the genes that they control and are often hidden within intergenic regions or in introns of other genes. The development of methods that enable mapping of regions of open chromatin genome wide has greatly advanced the identification and characterisation of these elements. Here we use DNase I hypersensitivity mapping followed by deep sequencing (DNase-seq) to generate a map of open chromatin in primary human tracheal epithelial (HTE) cells and use bioinformatic approaches to characterise the distribution of these sites within the genome and with respect to gene promoters, intronic and intergenic regions. Genes with HTE-selective open chromatin at their promoters were associated with multiple pathways of epithelial function and differentiation. The data predict novel cell-type-specific regulatory elements for genes involved in HTE cell function, such as structural proteins and ion channels, and the transcription factors that may interact with them to control gene expression. Moreover, the map of open chromatin can identify the location of potentially critical regulatory elements in genome-wide association studies (GWAS) in which the strongest association is with single nucleotide polymorphisms in non-coding regions of the genome. We demonstrate its relevance to a recent GWAS that identifies modifiers of cystic fibrosis lung disease severity. Since HTE cells have many functional similarities with bronchial epithelial cells and other differentiated cells in the respiratory epithelium, these data are of direct relevance to elucidating the molecular basis of normal lung function and lung disease.
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影响因子：
3.7
作者：
Michel S;Liang L;Depner M;Klopp N;Ruether A;Kumar A;Schedel M;Vogelberg C;von Mutius E;von Berg A;Bufe A;Rietschel E;Heinzmann A;Laub O;Simma B;Frischer T;Genuneit J;Gut IG;Schreiber S;Lathrop M;Illig T;Kabesch M
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作者：
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通讯作者：
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DOI：
10.1164/rccm.200708-1233oc
发表时间：
2008-04-01
影响因子：
24.7
作者：
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Boucher, Richard C.
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影响因子：
30.8
作者：
Gaulton, Kyle J.;Nammo, Takao;Pasquali, Lorenzo;Simon, Jeremy M.;Giresi, Paul G.;Fogarty, Marie P.;Panhuis, Tami M.;Mieczkowski, Piotr;Secchi, Antonio;Bosco, Domenico;Berney, Thierry;Montanya, Eduard;Mohlke, Karen L.;Lieb, Jason D.;Ferrer, Jorge
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影响因子：
7
作者：
Boyle, Alan P.;Song, Lingyun;Furey, Terrence S.
通讯作者：
Furey, Terrence S.