title: Cis-regulatory mechanisms governing stem and progenitor cell transitions.
abstract: 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.
authors.affiliation: Carbone Cancer Center, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. ; University of Wisconsin-Madison Blood Research Program, Madison, WI 53705, USA.
authors.forename: Kirby D
authors.initials: KD
authors.lastname: Johnson
authors.affiliation: University of Wisconsin-Madison Blood Research Program, Madison, WI 53705, USA. ; McArdle Laboratory for Cancer Research, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Kong
authors.affiliation: Carbone Cancer Center, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. ; University of Wisconsin-Madison Blood Research Program, Madison, WI 53705, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: University of Wisconsin-Madison Blood Research Program, Madison, WI 53705, USA. ; McArdle Laboratory for Cancer Research, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Yuan-I
authors.initials: YI
authors.lastname: Chang
authors.affiliation: Carbone Cancer Center, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. ; University of Wisconsin-Madison Blood Research Program, Madison, WI 53705, USA.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Hewitt
authors.affiliation: Carbone Cancer Center, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. ; University of Wisconsin-Madison Blood Research Program, Madison, WI 53705, USA.
authors.forename: Rajendran
authors.initials: R
authors.lastname: Sanalkumar
authors.affiliation: Carbone Cancer Center, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. ; University of Wisconsin-Madison Blood Research Program, Madison, WI 53705, USA.
authors.forename: Rajalekshmi
authors.initials: R
authors.lastname: Prathibha
authors.affiliation: Department of Pathology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Ranheim
authors.affiliation: Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.
authors.forename: Colin N
authors.initials: CN
authors.lastname: Dewey
authors.affiliation: University of Wisconsin-Madison Blood Research Program, Madison, WI 53705, USA. ; McArdle Laboratory for Cancer Research, 1111 Highland Avenue, Madison, WI 53705, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Carbone Cancer Center, Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. ; University of Wisconsin-Madison Blood Research Program, Madison, WI 53705, USA.
authors.forename: Emery H
authors.initials: EH
authors.lastname: Bresnick
keywords: GATA factor; GATA-2; cis-element; differentiation; hematopoiesis; myeloid; progenitor; stem cell; transcriptome