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

17 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 1 2015
Externally publishedYes

Fingerprint

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, 01.09.2015.

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.
@article{5ff78015c06547a2ab7fd1a9657e9c18,
title = "Cis-regulatory mechanisms governing stem and progenitor cell transitions",
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.",
author = "Johnson, {Kirby D.} and Guangyao Kong and Xin Gao and Chang, {Yuan I.} and Hewitt, {Kyle J} and Rajendran Sanalkumar and Rajalekshmi Prathibha and Ranheim, {Erik A.} and Dewey, {Colin N.} and Jing Zhang and Bresnick, {Emery H.}",
year = "2015",
month = "9",
day = "1",
doi = "10.1126/sciadv.1500503",
language = "English (US)",
volume = "1",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "8",

}

TY - JOUR

T1 - Cis-regulatory mechanisms governing stem and progenitor cell transitions

AU - Johnson, Kirby D.

AU - Kong, Guangyao

AU - Gao, Xin

AU - Chang, Yuan I.

AU - Hewitt, Kyle J

AU - Sanalkumar, Rajendran

AU - Prathibha, Rajalekshmi

AU - Ranheim, Erik A.

AU - Dewey, Colin N.

AU - Zhang, Jing

AU - Bresnick, Emery H.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84960828861&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84960828861&partnerID=8YFLogxK

U2 - 10.1126/sciadv.1500503

DO - 10.1126/sciadv.1500503

M3 - Article

VL - 1

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 8

M1 - e1500503

ER -