Cis-regulatory mechanisms governing stem and progenitor cell transitions

Kirby D. Johnson, Guangyao Kong, Xin Gao, Yuan I. Chang, Kyle J. Hewitt, Rajendran Sanalkumar, Rajalekshmi Prathibha, Erik A. Ranheim, Colin N. Dewey, Jing Zhang, Emery H. Bresnick

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere1500503
JournalScience Advances
Volume1
Issue number8
DOIs
StatePublished - Sep 2015

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Proto-Oncogenes
Acute Myeloid Leukemia
Stem Cells
Embryonic Structures
Encyclopedias
Mutation
Internal-External Control
Myelodysplastic Syndromes
Hematopoiesis
Hematopoietic Stem Cells
Transcriptome
Anemia
Phenotype

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Johnson, K. D., Kong, G., Gao, X., Chang, Y. I., Hewitt, K. J., Sanalkumar, R., ... Bresnick, E. H. (2015). Cis-regulatory mechanisms governing stem and progenitor cell transitions. Science Advances, 1(8), [e1500503]. https://doi.org/10.1126/sciadv.1500503

Cis-regulatory mechanisms governing stem and progenitor cell transitions. / Johnson, Kirby D.; Kong, Guangyao; Gao, Xin; Chang, Yuan I.; Hewitt, Kyle J.; Sanalkumar, Rajendran; Prathibha, Rajalekshmi; Ranheim, Erik A.; Dewey, Colin N.; Zhang, Jing; Bresnick, Emery H.

In: Science Advances, Vol. 1, No. 8, e1500503, 09.2015.

Research output: Contribution to journalArticle

Johnson, KD, Kong, G, Gao, X, Chang, YI, Hewitt, KJ, Sanalkumar, R, Prathibha, R, Ranheim, EA, Dewey, CN, Zhang, J & Bresnick, EH 2015, 'Cis-regulatory mechanisms governing stem and progenitor cell transitions', Science Advances, vol. 1, no. 8, e1500503. https://doi.org/10.1126/sciadv.1500503
Johnson, Kirby D. ; Kong, Guangyao ; Gao, Xin ; Chang, Yuan I. ; Hewitt, Kyle J. ; Sanalkumar, Rajendran ; Prathibha, Rajalekshmi ; Ranheim, Erik A. ; Dewey, Colin N. ; Zhang, Jing ; Bresnick, Emery H. / Cis-regulatory mechanisms governing stem and progenitor cell transitions. In: Science Advances. 2015 ; Vol. 1, No. 8.
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