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Regulation of DYT1 gene expression by the Ets family of transcription factors
Author(s) -
Armata Ioanna A.,
Ananthanarayanan Meenakshisundaram,
Balasubramaniyan Natarajan,
Shashidharan Pullanipally
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05465.x
Subject(s) - biology , gene , transcriptional regulation , transcription (linguistics) , tata box , start codon , promoter , primer extension , genetics , microbiology and biotechnology , transcription factor , gene expression , in silico , regulation of gene expression , messenger rna , linguistics , philosophy
The DYT1 gene encodes for torsinA, a protein with widespread tissue distribution, involved in early onset dystonia (EOD). Numerous studies have focused on torsinA function but no information is available on its transcriptional regulation. We cloned mouse and human 5′‐upstream DYT1 DNA fragments, exhibiting high transcriptional activity, as well as tissue specificity. We identified a proximal minimal DYT1 promoter within −141 bp for mouse and −191 bp for human with respect to the ATG codon. Primer extension analysis indicated multiple transcription start sites. In silico analysis of approximately 500 bp 5′‐upstream DYT1 fragment demonstrated lack of a classical TATA or CAAT box and the presence of a highly conserved direct repeat of two Ets binding cores within −86 bp to −77 bp and −78 bp to −69 bp of the mouse and human DYT1 gene, respectively. A single or a two base nucleotide alteration within the downstream Ets core resulted in approximately 90% (mouse) or 45–60% (human) drop in activity. Interestingly, a 3‐bp distance increase between the two Ets cores dramatically decreased transcriptional activity which was partially restored when the distance was increased up to 10 bp. Ets‐like dominant negatives confirmed the Ets factors as DYT1 transcriptional activators.