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 cell cycle 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, ZAC is the best candidate so far for both disease conditions. In the present work, we delineated ZAC genomic organization and mapped its transcriptional start site. It is noteworthy that the ZAC promoter 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 ZAC imprinted allele. Our findings further strengthen the hypothesis that ZAC is the gene responsible for TNDM and suggest a novel mechanism for ZAC inactivation in breast tumors.
Varrault
A
A
UPR 9023 CNRS-Centre CNRS-INSERM de Pharmacologie-Endocrinologie-141, rue de la Cardonille, 34094 Montpellier Cedex 05, France. varrault@ccipe.montp.inserm.fr
Bilanges
B
B
Mackay
D J
DJ
Basyuk
E
E
Ahr
B
B
Fernandez
C
C
Robinson
D O
DO
Bockaert
J
J
Journot
L
L
D000483:Alleles; D018797:Cell Cycle Proteins / Q000235:genetics*; D002455:Cell Division; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6; D003001:Cloning, Molecular; D018899:CpG Islands; D019175:DNA Methylation; D003920:Diabetes Mellitus / Q000235:genetics*; D005091:Exons; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D018392:Genomic Imprinting; D006801:Humans; D007231:Infant, Newborn; D007438:Introns; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; C106464:PLAGL1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins