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Volume 271, Number 38, Issue of September 20, 1996 pp. 23126-23133
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

Genesis, a Winged Helix Transcriptional Repressor with Expression Restricted to Embryonic Stem Cells

(Received for publication, April 26, 1996, and in revised form, June 27, 1996)

Jill Sutton Dagger , Robert Costa § , Michael Klug par , Loren Field par , Dawei Xu Dagger , David A. Largaespada ''' , Colin F. Fletcher , Nancy A. Jenkins , Neal G. Copeland ''' , Michael Klemsz par and Robert Hromas Dagger par par

From the Dagger  Division of Hematology/Oncology and the Walther Oncology Center, IB 442, Indiana University Medical Center, Indianapolis, Indiana 46202-5121, the § Department of Biochemistry, University of Illinois College of Medicine, Chicago, Illinois 60612-7334, par  Krannert Institute of Cardiology, Indiana University Medical Center, Indianapolis, Indiana 46202, ''' Mammalian Genetics Laboratory, ABL-Basic Research Program, NCI, National Institutes of Health, Frederick Cancer Research and Development Center, Frederick, Maryland 21702, and the par  Department of Microbiology/Immunology, MS 252, Indiana University Medical Center, Indianapolis, Indiana 46202-5120

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.


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