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A short ultraconserved sequence drives transcription from an alternate FBN1 promoter

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons50196

Hecht,  Jochen
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50496

Robinson,  Peter N.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Zitation

Guo, G., Bauer, S., Hecht, J., Schulz, M. H., Busche, A., & Robinson, P. N. (2008). A short ultraconserved sequence drives transcription from an alternate FBN1 promoter. The International Journal of Biochemistry & Cell Biology, 40(4), 638-650. doi:10.1016/j.biocel.2007.09.004.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0010-8015-E
Zusammenfassung
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.