Characterisation of hormone responsive and negative regulatory elements in the human insulin gene enhancer
A hormone response element and a negative regulatory element upstream of the human insulin gene have been investigated. The hormone response element is located one kilobase upstream of the transcription start site. When isolated and placed upstream of a viral promoter, it has been found to increase transcription in response to retinoic acid and thyroid hormone. It is also able to mediate a transcriptional response to retinoic acid, and to the retinoic acid receptor in the context of the entire insulin gene promoter/enhancer region. This element is able to bind to members of the retinoid receptor family in vitro. Insulin gene transcription in isolated human islets of Langerhans was also shown to be upregulated by retinoic acid. The negative regulatory element within the human insulin gene enhancer lies between 279 and 258 base pairs upstream of the transcription start site, although it relies upon nearby insulin enhancer sequence in order to act upon a heterologous promoter. The transcriptional silencing properties of the negative element can be abolished by point mutations of critical residues. The element forms several complexes with nuclear proteins from an insulin producing cell line, one of which is related to the ubiquitous POU domain factor, Oct-1. The relevance of these findings to the control of insulin gene transcription is discussed.