Abstract
A novel member of the winged helix (formerly HNF-3/Forkhead) transcriptional regulatory family, termed Genesis, was isolated and characterized. Putative translation of the complete cDNA revealed the winged helix DNA binding domain to be centrally located within the protein, with regions on either side that contain known transcriptional regulatory motifs. Extensive Northern analysis of Genesis found that the message was exclusively expressed in embryonic stem cells or their malignant equivalent, embryonal carcinoma cells. The Genesis transcript was down-regulated when these cells were stimulated to differentiate. DNA sequences that Genesis protein would interact with were characterized and were found to contain a consensus similar to that found in an embryonic stem cell enhancer sequence. Co-transfection experiments revealed that Genesis is a transcriptional repressor. Genesis mapped to mouse chromosome 4 in a region syntenic with human chromosome 1p31, a site of nonrandom abnormalities in germ cell neoplasia, neuroblastoma, and acute lymphoblastic leukemia. Genesis is a candidate for regulating the phenotype of normal or malignant embryonic stem cells.
Highlights
Development is controlled by regulatory genes acting as genetic switches to stimulate cascades of gene expression, producing tissue and organismal phenotypes
The winged helix DNA binding domain of HFH-2 was isolated by polymerase chain reaction from genomic DNA, indicating that the winged helix domain existed as a single exon, but the entire cDNA was intractable to isolation
Genesis is a novel member of the winged helix transcriptional regulator family
Summary
Development is controlled by regulatory genes acting as genetic switches to stimulate cascades of gene expression, producing tissue and organismal phenotypes. In Drosophila these regulatory genes are often transcriptional regulators that initiate the gene cascade resulting in that embryonic stage’s phenotypic change and direct expression of the regulators important in the embryonic stage These transcriptional regulators fall into related families based on conserved structure in their DNA binding domain The winged helix domain of the hepatocyte nuclear factor 3 (HNF-3) proteins mediates binding to specific DNA sequences having the consensus A(A/ T)TRTT(G/T)RYTY [14] Several members of this family are essential for normal Drosophila development [12, 15]. A rat and mouse nude mutation disrupts the winged helix gene whn [20, 21]
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