A dinucleotide deletion in the ankyrin promoter alters gene expression, transcription initiation and TFIID complex formation in hereditary spherocytosis
| Autor: | Clara Wong, Patrick G. Gallagher, Douglas G. Nilson, Lisa Garrett-Beal, Jessica L. Weisbein, Stephan W. Eber, David M. Bodine |
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| Přispěvatelé: | University of Zurich, Gallagher, Patrick G |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Ankyrins
2716 Genetics (clinical) Transcription Genetic TATA box 610 Medicine & health Spherocytosis Hereditary Biology 142-005 142-005 Polymerase Chain Reaction 1311 Genetics ANK1 Genes Reporter Genetics 1312 Molecular Biology Ankyrin Humans Peptide Chain Initiation Translational Promoter Regions Genetic Molecular Biology Genetics (clinical) Polymorphism Single-Stranded Conformational DNA Primers Sequence Deletion chemistry.chemical_classification Base Composition Erythrocyte Membrane fungi Promoter General Medicine Molecular biology TATA Box TAF1 chemistry Gene Expression Regulation Transcription Factor TFIID 570 Life sciences biology Ankyrin repeat Transcription factor II A |
| Popis: | Ankyrin defects are the most common cause of hereditary spherocytosis (HS). In some HS patients, mutations in the ankyrin promoter have been hypothesized to lead to decreased ankyrin mRNA synthesis. The ankyrin erythroid promoter is a member of the most common class of mammalian promoters which lack conserved TATA, initiator or other promoter cis elements and have high G+C content, functional Sp1 binding sites and multiple transcription initiation sites. We identified a novel ankyrin gene promoter mutation, a TG deletion adjacent to a transcription initiation site, in a patient with ankyrin-linked HS and analyzed its effects on ankyrin expression. In vitro, the mutant promoter directed decreased levels of gene expression, altered transcription initiation site utilization and exhibited defective binding of TATA-binding protein (TBP) and TFIID complex formation. In a transgenic mouse model, the mutant ankyrin promoter led to abnormalities in gene expression, including decreased expression of a reporter gene and altered transcription initiation site utilization. These data indicate that the mutation alters ankyrin gene transcription and contributes to the HS phenotype by decreasing ankyrin gene synthesis via disruption of TFIID complex interactions with the ankyrin core promoter. These studies support the model that in promoters that lack conserved cis elements, the TFIID complex directs preinitiation complex formation at specific sites in core promoter DNA and provide the first evidence that disruption of TBP binding and TFIID complex formation in this type of promoter leads to alterations in start site utilization, decreased gene expression and a disease phenotype in vivo. |
| Databáze: | OpenAIRE |
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