Characterization of the methylation-sensitive promoter of the imprinted ZAC gene supports its role in transient neonatal diabetes mellitus

ZAC is a recently isolated zinc finger protein that induces apoptosis and c ell cycle arrest. The corresponding gene is imprinted maternally through an unknown mechanism and maps to 6q24-q25, within the minimal interval harbor ing the gene responsible for transient neonatal diabetes mellitus (TNDM) an d a tumor suppressor gene involved in breast cancer, Because of its functio nal properties, imprinting status, and expression pattern in mammary cell l ines and tumors, ZAC is the best candidate so far for both disease conditio ns. In the present work, we delineated ZAC genomic organization and mapped its transcriptional start site. It is noteworthy that the ZAC promoter loca lized to the CpG island harboring the methylation imprint associated with T NDM and methylation of this promoter silenced its activity. These data indi cate that the methylation mark may have a direct effect on the silencing of the ZAC imprinted allele, Our findings further strengthen the hypothesis t hat ZAC is the gene responsible for TNDM and suggest a novel mechanism for ZAC inactivation in breast tumors.