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Human Molecular Genetics Advance Access published online on May 24, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl133
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received January 26, 2006
Revised April 4, 2006
Accepted May 17, 2006

Article

Distant conserved sequences flanking endothelial-specific promoters contain tissue-specific DNase-hypersensitive sites and overrepresented motifs

John A. Bernat 1, Gregory E. Crawford 2, Aleksey Y. Ogurtsov 3, Francis S. Collins 2, David Ginsburg 4 *, and Alexey S. Kondrashov 3

1 Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
2 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
3 National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD 20894, USA
4 Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Howard Hughes Medical Institute, and Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA

* To whom correspondence should be addressed.
David Ginsburg, E-mail: ginsburg{at}umich.edu


  Abstract

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 noncoding 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, while only 16% are HS in control fibroblasts. A search for short sequence patterns revealed a number of motifs which are overrepresented in EC-CNSs relative to CNSs from the control gene sets. In particular, the motif SAGGAAR is strongly and consistently overrepresented among EC-CNSs, and is more overrepresented 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.


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