Comparative Analysis of Insulin Gene Promoters: Implications for Diabetes Research

Colin W. Hay; Kevin Docherty

Disclosures

Diabetes. 2006;55(12):3201-3213. 

In This Article

Conclusion

The extraordinary synteny of insulin genes from zebrafish to human substantiates the key importance of the insulin hormone product. Comparison of insulin promoters spanning 450 million years of evolution has permitted identification of the central regulatory elements as well as several valuable observations.

  1. The transcription factor PDX-1 emerges as one of the fundamental regulators of insulin expression for several reasons: all promoters have at least one A box with A3 being the most conserved, the weaker PDX-1-binding GG boxes also form ECRs with GG2 being the more conserved, and the transcription factor is known to interact with MafA and E47/ß2.

  2. The other strongly conserved regulatory elements of C1, E1, and the conserved CRE site attest to the importance of MafA, E47/ß2, and cAMP-associated regulation. Of these regulatory elements, the CRE site is unusual due to the remarkable degree of variability and extensive array of associating transcription factors.

  3. Regulatory element conservation is not limited to the consensus sequences as the flanking regions also contribute to ECRs. This is true of regulatory elements with both short and long recognition sequences indicating that flanking regions are necessary for transcription factor specificity and binding. This may be of particular consequence for the capricious CRE sites while the asymmetrical nature of the conserved A3 box flanking regions may reflect directional binding of PDX-1.

  4. Within mammals, dog stands out due to its much greater homology to humans. The similarities include higher percentage identity, possessing more PDX-1–binding A boxes and GG elements, and having a CRE site that is identical to human. It is interesting to speculate whether these likenesses between a carnivore and omnivore correlate to the increased contribution of meat in the human diet over evolutionary time compared with other primates.

  5. The chicken and zebrafish insulin promoters bear no obvious homology with mammals and exhibit a dearth of readily discernible regulatory elements.

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