GENESIS, A WINGED HELIX TRANSCRIPTIONAL REPRESSOR WITH EXPRESSION RESTRICTED TO EMBRYONIC STEM-CELLS

A novel member of the winged helix (formerly HNF-3/Forkhead) transcrip tional regulatory family, termed Genesis, was isolated and characteriz ed. Putative translation of the complete cDNA revealed the winged heli x DNA binding domain to be centrally located within the protein, with regions on either side that contain known transcriptional regulatory m otifs. Extensive Northern analysis of Genesis found that the message w as exclusively expressed in embryonic stem cells or their malignant eq uivalent, embryonal carcinoma cells. The Genesis transcript was down-r egulated when these cells were stimulated to differentiate. DNA sequen ces that Genesis protein would interact with were characterized and we re found to contain a consensus similar to that found in an embryonic stem cell enhancer sequence, Go-transfection experiments revealed that Genesis is a transcriptional repressor. Genesis mapped to mouse chrom osome 4 in a region syntenic with human chromosome 1p31, a site of non random abnormalities in germ cell neoplasia, neuroblastoma, and acute lymphoblastic leukemia, Genesis is a candidate for regulating the phen otype of normal or malignant embryonic stem cells.