Characterization of the Methylation-sensitive Promoter of the Imprinted ZACGene Supports Its Role in Transient Neonatal Diabetes Mellitus*

ZAC is a recently isolated zinc finger protein that induces apoptosis and cellcycle arrest. The corresponding gene is imprinted maternally through an unknown mechanism and maps to 6q24–q25, within the minimal interval harboring the gene responsible for transient neonatal diabetes mellitus (TNDM) and a tumor suppressor gene involved in breast cancer. Because of its functional properties, imprinting status, and expression pattern in mammary cell lines and tumors,ZACis the best candidate so far for both disease conditions. In the present work, we delineated ZACgenomic organization and mapped its transcriptional start site. It is noteworthy that the ZACpromoter localized to the CpG island harboring the methylation imprint associated with TNDM and methylation of this promoter silenced its activity. These data indicate that the methylation mark may have a direct effect on the silencing of the ZACimprinted allele. Our findings further strengthen the hypothesis that ZACis the gene responsible for TNDM and suggest a novel mechanism for ZACinactivation in breast tumors.