| First Author | Johnson KD | Year | 2015 |
| Journal | Sci Adv | Volume | 1 |
| Issue | 8 | Pages | e1500503 |
| PubMed ID | 26601269 | Mgi Jnum | J:259078 |
| Mgi Id | MGI:6140856 | Doi | 10.1126/sciadv.1500503 |
| Citation | Johnson KD, et al. (2015) Cis-regulatory mechanisms governing stem and progenitor cell transitions. Sci Adv 1(8):e1500503 |
| abstractText | Cis-element encyclopedias provide information on phenotypic diversity and disease mechanisms. Although cis-element 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. |
