Distant conserved sequences flanking endothelial-specific promoters contain tissue-specific DNase-hypersensitive sites and over-represented motifs
Distant conserved sequences flanking endothelial-specific promoters contain tissue-specific DNase-hypersensitive sites and over-represented motifs
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DOI：
10.1093/hmg/ddl133
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发表时间：
2006-07-01
影响因子：
3.5
通讯作者：
Kondrashov, Alexey S.
中科院分区：
文献类型：
--
作者：
Bernat, John A.;Crawford, Gregory E.;Kondrashov, Alexey S.
基因的转录调控是一个复杂的过程，特别是对于表现出组织特异性表达模式的基因。我们研究了28个主要在内皮细胞中表达的基因，另外28个在培养的内皮细胞中高度表达但不完全表达的基因，以及三个对照组，包括在内皮细胞中不表达的基因，在神经组织中表达的基因和管家基因。对于每个基因，我们鉴定了长度为50至> 1000个核苷酸的保守非编码序列（CNS），其位于上游基因间区域（从转录起始上游500至远至200 000个核苷酸）内或第一内含子内。作为一个功能测试，我们测定了从内皮细胞特异性基因（EC-CNSs）的DNase超敏性的一组CNSs。在262个远端EC-CNS中，33%的内皮细胞是高敏的（HS），而对照成纤维细胞中只有16%是HS。搜索短序列模式揭示了一些图案，这些图案在EC-CNSs中相对于来自对照基因组的CNSs过度表达。特别地，基序SAGGAAR在EC-CNS中强烈且一致地过度表达，并且在HS CNS中比在非HS CNS中更过度表达。含有该基序的CNS并不比平均CNS更接近启动子。该基序包含来自转录因子Ets家族的结合位点的核心元件。因此，来自该家族的一个或几个因子可能在内皮基因表达的调节中起关键作用。
The transcriptional regulation of genes is a complex process, particularly for genes exhibiting a tissue-specific pattern of expression. We studied 28 genes that are expressed primarily in endothelial cells, another 28 genes that are expressed highly, but not exclusively, in cultured endothelial cells, and three control sets, consisting of genes not expressed in endothelium, genes expressed in neural tissues and housekeeping genes. For each gene, we identified conserved non-coding sequences (CNSs) of lengths 50 to > 1000 nucleotides, located within the upstream intergenic region (from 500 to as far as 200 000 nucleotides upstream from the transcription start) or within the first intron. As a functional test, we assayed the CNSs from the set of endothelial cell-specific genes (EC-CNSs) for DNase hypersensitivity. Among 262 distant EC-CNSs, 33% are hypersensitive (HS) in endothelial cells, whereas only 16% are HS in control fibroblasts. A search for short sequence patterns revealed a number of motifs which are over-represented in EC-CNSs relative to CNSs from the control gene sets. In particular, the motif SAGGAAR is strongly and consistently over-represented among EC-CNSs, and is more over-represented in HS CNSs than in non-HS CNSs. CNSs which contain this motif are no closer to the promoter than an average CNS. This motif contains the core element of binding sites from the Ets family of transcription factors. Thus, one or several factors from this family may play a key role in the regulation of endothelial gene expression.