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Title: Identification of GATA2 and AP-1 activator elements within the enhancer VNTR occurring in intron 5 of the human SIRT3 gene

Author
item BELLIZZI, DINA - University Of Calabria
item COVELLO, GIUSEPPINA - University Of Calabria
item DI CIANNI, FAUSTA - University Of Calabria
item TONG, QIANG - Children'S Nutrition Research Center (CNRC)
item DE BENEDICTIS, GIOVANNA - University Of Calabria

Submitted to: Molecules and Cells
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/30/2009
Publication Date: 8/20/2009
Citation: Bellizzi, D., Covello, G., Di Cianni, F., Tong, Q., De Benedictis, G. 2009. Identification of GATA2 and AP-1 activator elements within the enhancer VNTR occurring in intron 5 of the human SIRT3 gene. Molecules and Cells. 28:87-92.

Interpretive Summary: Human SIRT3 gene was previously found to be associated with longevity. More specifically, a specific change of DNA within human SIRT3 gene (T to C substitution in SIRT3 gene intron) has been linked with longevity. This DNA change may affect the binding of GATA transcription factors to this stretch of DNA. We confirmed that both GATA2 and c-Jun/c-Fos factors are able to bind this stretch of DNA. Moreover, co-expression of GATA2 and c-Jun/c-Fos factors additively increases the enhancer activity of this piece of DNA. Our finding suggested that alteration of SIRT3 gene may affect the binding of GATA factors and consequently the expression of SIRT3.

Technical Abstract: Human SIRT3 gene contains an intronic VNTR enhancer. A T > C transition occurring in the second repeat of each VNTR allele implies the presence/absence of a putative GATA binding motif. A partially overlapping AP-1 site, not affected by the transition, was also identified. Aims of the present study were: 1) to verify if GATA and AP-1 sites could bind GATA2 and c-Jun/c-Fos factors, respectively; 2) to investigate whether such sites modulate the enhancer activity of the SIRT3-VNTR alleles. DAPA assay proved that GATA2 and c-Jun/c-Fos factors are able to bind the corresponding sites. Moreover, co-transfection experiments showed that the over-expression of GATA2 and c-Jun/c-Fos factors boosts the VNTR enhancer activity in an allelic-specific way. Furthermore, we established that GATA2 and c-Jun/c-Fos act additively in modulating the SIRT3-VNTR enhancer function. Therefore, GATA2 and AP-1 are functional sites and the T S> C transition of the second VNTR repeat affects their activity.