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          Institute: MPI für molekulare Genetik     Collection: Department of Computational Molecular Biology     Display Documents



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ID: 335978.0, MPI für molekulare Genetik / Department of Computational Molecular Biology
A short ultraconserved sequence drives transcription from an alternate FBN1 promoter
Authors:Guo, Gao; Bauer, Sebastian; Hecht, Jochen; Schulz, Marcel H.; Busche, Andreas; Robinson, Peter N.
Language:English
Date of Publication (YYYY-MM-DD):2008-04-01
Title of Journal:The International Journal of Biochemistry & Cell Biology
Journal Abbrev.:Int. J. Biochem. Cell Biol.
Volume:40
Issue / Number:4
Start Page:638
End Page:650
Copyright:© 2007 Elsevier Ltd All rights reserved.
Review Status:not specified
Audience:Experts Only
Abstract / Description:FBN1, the gene mutated in Marfan syndrome, encodes fibrillin-1, a large glycoprotein component of the extracellular microfibrils. Human FBN1 has three untranslated upstream exons, and homologous sequences can be identified in a number of mammalian species.

In this work, we have used functional assays to characterize the FBN1 upstream region. Sequences upstream of exon 1 and at least two of the upstream untranslated exons were shown to possess promoter activity in vitro. The strongest activity in luciferase assays was shown for sequences upstream of the untranslated exon A. Sequence analysis of the sequences in and upstream of exon A in humans and six other mammalian species demonstrated several highly conserved potential cis-acting sequences as well as a 66-basepair (bp) ultraconserved sequence with nearly perfect conservation in the seven species. The ultraconserved sequence contains an initiator element (Inr), a downstream promoter element (DPE), and a 10-bp palindromic element.

Mutational assays showed that both the Inr and the DPE are critical for full promoter activity. A mutation of the 10-bp palindromic element completely abolished basal promoter activity. The element was shown to bind specifically to an unknown nuclear protein by electrophoretic mobility shift assay.

Ultraconservation within an alternate promoter has not been previously reported. We suggest that the ultraconservation may reflect the importance of finely tuned regulation of alternate transcription of FBN1 and that the sequences involved have been under negative selective pressure for at least the last 180 million years of mammalian evolution.
Free Keywords:Fibrillin-1; Marfan syndrome; Ultraconservation; Downstream promoter element; Luciferase
Comment of the Author/Creator:Corresponding author. Tel.: +49 30 450 569124; fax: +49 30 450 569915.
Tel.: +49 30 450 569124; fax: +49 30 450 569915.
Sequence motifs are shown using the IUPAC nucleotide ambiguity code, K=G/T, M=A/C, N=A/C/G/T, R=A/G, S=C/G, V=A/C/G, W=A/T, Y=C/T.
Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.biocel.2007.09.004.
External Publication Status:published
Document Type:Article
Communicated by:Martin Vingron
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Institute for Medical Genetics, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany;
2.Berlin Brandenburg Center for Regenerative Therapies, Charité Universitätsmedizin, Berlin, Germany.
Identifiers:ISSN:1357-2725
DOI:10.1016/j.biocel.2007.09.004
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