Cis-regulatory mechanisms governing stem and progenitor cell transitions

Cis-element encyclopedias provide information on phenotypic diversity and disease mechanisms. Although ciselement polymorphisms and mutations are instructive, deciphering function remains challenging. Mutation of an intronic GATA motif (+ 9.5) in GATA2, encoding a master regulator of hematopoiesis, underlies an immunodeficiency associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Whereas an inversion relocalizes another GATA2 cis-element(- 77) to the proto-oncogene EVI1, inducing EVI1 expression and AML, whether this reflects ectopic or physiological activity is unknown. We describe a mouse strain that decouples - 77 function from proto-oncogene deregulation. The - 77(-/-)mice exhibited a novel phenotypic constellation including late embryonic lethality and anemia. The - 77 established a vital sector of the myeloid progenitor transcriptome, conferring multipotentiality. Unlike the + 9.5(-/-) embryos, hematopoietic stem cell genesis was unaffected in - 77(-/-) embryos. These results illustrate a paradigm in which cis-elements in a locus differentially control stem and progenitor cell transitions, and therefore the individual cis-element alterations cause unique and overlapping disease phenotypes.