LymphedemaV1, Ncbi, Curation, bibRecord, 005148

Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity

Identifieur interne : 005148 ( Ncbi/Curation ); précédent : 005147; suivant : 005149

Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity

Auteurs : Kirby D. Johnson [États-Unis] ; Amy P. Hsu [États-Unis] ; Myung-Jeom Ryu [États-Unis] ; Jinyong Wang [États-Unis] ; Xin Gao [États-Unis] ; Meghan E. Boyer [États-Unis] ; Yangang Liu [États-Unis] ; Youngsook Lee [États-Unis] ; Katherine R. Calvo [États-Unis] ; Sunduz Keles [États-Unis] ; Jing Zhang [États-Unis] ; Steven M. Holland [États-Unis] ; Emery H. Bresnick [États-Unis]

Source :

The Journal of Clinical Investigation [ 0021-9738 ] ; 2012.

RBID : PMC:3461907

Descripteurs français

KwdFr :
- Animaux, Cellules souches hématopoïétiques (anatomopathologie), Données de séquences moléculaires, Déficits immunitaires (génétique), Délétion de séquence, Développement embryonnaire (génétique), Endothélium vasculaire (métabolisme), Facteur de transcription GATA-2 (), Facteur de transcription GATA-2 (déficit), Facteur de transcription GATA-2 (génétique), Facteur de transcription GATA-2 (physiologie), Foie (cytologie), Foie (embryologie), Gènes létaux, Génotype, Humains, Hématopoïèse (génétique), Hématopoïèse (physiologie), Hémorragie (embryologie), Hémorragie (génétique), Infections à Mycobacterium (étiologie), Prédisposition génétique à une maladie, Souris, Syndromes myélodysplasiques (), Syndromes myélodysplasiques (génétique), Séquence nucléotidique, Vaisseaux sanguins (anatomopathologie), Vaisseaux sanguins (embryologie), Éléments E-box, Éléments de régulation transcriptionnelle.
MESH :
- anatomopathologie : Cellules souches hématopoïétiques, Vaisseaux sanguins.
- cytologie : Foie.
- déficit : Facteur de transcription GATA-2.
- embryologie : Foie, Hémorragie, Vaisseaux sanguins.
- génétique : Déficits immunitaires, Développement embryonnaire, Facteur de transcription GATA-2, Hématopoïèse, Hémorragie, Syndromes myélodysplasiques.
- métabolisme : Endothélium vasculaire.
- physiologie : Facteur de transcription GATA-2, Hématopoïèse.
- étiologie : Infections à Mycobacterium.
- Animaux, Données de séquences moléculaires, Délétion de séquence, Facteur de transcription GATA-2, Gènes létaux, Génotype, Humains, Prédisposition génétique à une maladie, Souris, Syndromes myélodysplasiques, Séquence nucléotidique, Éléments E-box, Éléments de régulation transcriptionnelle.

English descriptors

KwdEn :
- Animals, Base Sequence, Blood Vessels (embryology), Blood Vessels (pathology), E-Box Elements, Embryonic Development (genetics), Endothelium, Vascular (metabolism), GATA2 Transcription Factor (chemistry), GATA2 Transcription Factor (deficiency), GATA2 Transcription Factor (genetics), GATA2 Transcription Factor (physiology), Genes, Lethal, Genetic Predisposition to Disease, Genotype, Hematopoiesis (genetics), Hematopoiesis (physiology), Hematopoietic Stem Cells (pathology), Hemorrhage (embryology), Hemorrhage (genetics), Humans, Immunologic Deficiency Syndromes (genetics), Liver (cytology), Liver (embryology), Mice, Molecular Sequence Data, Mycobacterium Infections (etiology), Myelodysplastic Syndromes (complications), Myelodysplastic Syndromes (genetics), Regulatory Elements, Transcriptional, Sequence Deletion.
MESH :
- chemical , chemistry : GATA2 Transcription Factor.
- chemical , deficiency : GATA2 Transcription Factor.
- complications : Myelodysplastic Syndromes.
- cytology : Liver.
- embryology : Blood Vessels, Hemorrhage, Liver.
- etiology : Mycobacterium Infections.
- genetics : Embryonic Development, GATA2 Transcription Factor, Hematopoiesis, Hemorrhage, Immunologic Deficiency Syndromes, Myelodysplastic Syndromes.
- metabolism : Endothelium, Vascular.
- pathology : Blood Vessels, Hematopoietic Stem Cells.
- chemical , physiology : GATA2 Transcription Factor, Hematopoiesis.
- Animals, Base Sequence, E-Box Elements, Genes, Lethal, Genetic Predisposition to Disease, Genotype, Humans, Mice, Molecular Sequence Data, Regulatory Elements, Transcriptional, Sequence Deletion.

Abstract

Haploinsufficiency for GATA2 causes human immunodeficiency syndromes characterized by mycobacterial infection, myelodysplasia, lymphedema, or aplastic anemia that progress to myeloid leukemia. GATA2 encodes a master regulator of hematopoiesis that is also linked to endothelial biology. Though the disease-causing mutations commonly occur in the GATA-2 DNA binding domain, we identified a patient with mycobacterial infection and myelodysplasia who had an uncharacterized heterozygous deletion in a GATA2cis-element consisting of an E-box and a GATA motif. Targeted deletion of the equivalent murine element to yield homozygous mutant mice revealed embryonic lethality later than occurred with global Gata2 knockout, hematopoietic stem/progenitor cell depletion, and impaired vascular integrity. Heterozygous mutant mice were viable, but embryos exhibited deficits in definitive, but not primitive, hematopoietic stem/progenitor activity and reduced expression of Gata2 and its target genes. Mechanistic analysis revealed disruption of the endothelial cell transcriptome and loss of vascular integrity. Thus, the composite element disrupted in a human immunodeficiency is essential for establishment of the murine hematopoietic stem/progenitor cell compartment in the fetal liver and for essential vascular processes.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461907

DOI: 10.1172/JCI61623
PubMed: 22996659
PubMed Central: 3461907

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PMC:3461907

Le document en format XML

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-element mutated in <italic>GATA2</italic>-dependent immunodeficiency governs hematopoiesis and vascular integrity
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-element mutated in <italic>GATA2</italic>-dependent immunodeficiency governs hematopoiesis and vascular integrity
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<author><name sortKey="Johnson, Kirby D" sort="Johnson, Kirby D" uniqKey="Johnson K" first="Kirby D." last="Johnson">Kirby D. Johnson</name>
<affiliation wicri:level="2"><nlm:aff id="JCI61623">Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.</nlm:aff>
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<author><name sortKey="Gao, Xin" sort="Gao, Xin" uniqKey="Gao X" first="Xin" last="Gao">Xin Gao</name>
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<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin</wicri:regionArea>
<placeName><region type="state">Wisconsin</region>
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<author><name sortKey="Liu, Yangang" sort="Liu, Yangang" uniqKey="Liu Y" first="Yangang" last="Liu">Yangang Liu</name>
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<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
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<author><name sortKey="Lee, Youngsook" sort="Lee, Youngsook" uniqKey="Lee Y" first="Youngsook" last="Lee">Youngsook Lee</name>
<affiliation wicri:level="2"><nlm:aff id="JCI61623">Department of Cell and Regenerative Biology, Wisconsin Institutes for Medical Research, UW Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
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<author><name sortKey="Calvo, Katherine R" sort="Calvo, Katherine R" uniqKey="Calvo K" first="Katherine R." last="Calvo">Katherine R. Calvo</name>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Base Sequence</term>
<term>Blood Vessels (embryology)</term>
<term>Blood Vessels (pathology)</term>
<term>E-Box Elements</term>
<term>Embryonic Development (genetics)</term>
<term>Endothelium, Vascular (metabolism)</term>
<term>GATA2 Transcription Factor (chemistry)</term>
<term>GATA2 Transcription Factor (deficiency)</term>
<term>GATA2 Transcription Factor (genetics)</term>
<term>GATA2 Transcription Factor (physiology)</term>
<term>Genes, Lethal</term>
<term>Genetic Predisposition to Disease</term>
<term>Genotype</term>
<term>Hematopoiesis (genetics)</term>
<term>Hematopoiesis (physiology)</term>
<term>Hematopoietic Stem Cells (pathology)</term>
<term>Hemorrhage (embryology)</term>
<term>Hemorrhage (genetics)</term>
<term>Humans</term>
<term>Immunologic Deficiency Syndromes (genetics)</term>
<term>Liver (cytology)</term>
<term>Liver (embryology)</term>
<term>Mice</term>
<term>Molecular Sequence Data</term>
<term>Mycobacterium Infections (etiology)</term>
<term>Myelodysplastic Syndromes (complications)</term>
<term>Myelodysplastic Syndromes (genetics)</term>
<term>Regulatory Elements, Transcriptional</term>
<term>Sequence Deletion</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Cellules souches hématopoïétiques (anatomopathologie)</term>
<term>Données de séquences moléculaires</term>
<term>Déficits immunitaires (génétique)</term>
<term>Délétion de séquence</term>
<term>Développement embryonnaire (génétique)</term>
<term>Endothélium vasculaire (métabolisme)</term>
<term>Facteur de transcription GATA-2 ()</term>
<term>Facteur de transcription GATA-2 (déficit)</term>
<term>Facteur de transcription GATA-2 (génétique)</term>
<term>Facteur de transcription GATA-2 (physiologie)</term>
<term>Foie (cytologie)</term>
<term>Foie (embryologie)</term>
<term>Gènes létaux</term>
<term>Génotype</term>
<term>Humains</term>
<term>Hématopoïèse (génétique)</term>
<term>Hématopoïèse (physiologie)</term>
<term>Hémorragie (embryologie)</term>
<term>Hémorragie (génétique)</term>
<term>Infections à Mycobacterium (étiologie)</term>
<term>Prédisposition génétique à une maladie</term>
<term>Souris</term>
<term>Syndromes myélodysplasiques ()</term>
<term>Syndromes myélodysplasiques (génétique)</term>
<term>Séquence nucléotidique</term>
<term>Vaisseaux sanguins (anatomopathologie)</term>
<term>Vaisseaux sanguins (embryologie)</term>
<term>Éléments E-box</term>
<term>Éléments de régulation transcriptionnelle</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>GATA2 Transcription Factor</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="deficiency" xml:lang="en"><term>GATA2 Transcription Factor</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Cellules souches hématopoïétiques</term>
<term>Vaisseaux sanguins</term>
</keywords>
<keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Myelodysplastic Syndromes</term>
</keywords>
<keywords scheme="MESH" qualifier="cytologie" xml:lang="fr"><term>Foie</term>
</keywords>
<keywords scheme="MESH" qualifier="cytology" xml:lang="en"><term>Liver</term>
</keywords>
<keywords scheme="MESH" qualifier="déficit" xml:lang="fr"><term>Facteur de transcription GATA-2</term>
</keywords>
<keywords scheme="MESH" qualifier="embryologie" xml:lang="fr"><term>Foie</term>
<term>Hémorragie</term>
<term>Vaisseaux sanguins</term>
</keywords>
<keywords scheme="MESH" qualifier="embryology" xml:lang="en"><term>Blood Vessels</term>
<term>Hemorrhage</term>
<term>Liver</term>
</keywords>
<keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Mycobacterium Infections</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Embryonic Development</term>
<term>GATA2 Transcription Factor</term>
<term>Hematopoiesis</term>
<term>Hemorrhage</term>
<term>Immunologic Deficiency Syndromes</term>
<term>Myelodysplastic Syndromes</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Déficits immunitaires</term>
<term>Développement embryonnaire</term>
<term>Facteur de transcription GATA-2</term>
<term>Hématopoïèse</term>
<term>Hémorragie</term>
<term>Syndromes myélodysplasiques</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Endothelium, Vascular</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Endothélium vasculaire</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Blood Vessels</term>
<term>Hematopoietic Stem Cells</term>
</keywords>
<keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Facteur de transcription GATA-2</term>
<term>Hématopoïèse</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>GATA2 Transcription Factor</term>
<term>Hematopoiesis</term>
</keywords>
<keywords scheme="MESH" qualifier="étiologie" xml:lang="fr"><term>Infections à Mycobacterium</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Base Sequence</term>
<term>E-Box Elements</term>
<term>Genes, Lethal</term>
<term>Genetic Predisposition to Disease</term>
<term>Genotype</term>
<term>Humans</term>
<term>Mice</term>
<term>Molecular Sequence Data</term>
<term>Regulatory Elements, Transcriptional</term>
<term>Sequence Deletion</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Données de séquences moléculaires</term>
<term>Délétion de séquence</term>
<term>Facteur de transcription GATA-2</term>
<term>Gènes létaux</term>
<term>Génotype</term>
<term>Humains</term>
<term>Prédisposition génétique à une maladie</term>
<term>Souris</term>
<term>Syndromes myélodysplasiques</term>
<term>Séquence nucléotidique</term>
<term>Éléments E-box</term>
<term>Éléments de régulation transcriptionnelle</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Haploinsufficiency for <italic>GATA2</italic>
 causes human immunodeficiency syndromes characterized by mycobacterial infection, myelodysplasia, lymphedema, or aplastic anemia that progress to myeloid leukemia. <italic>GATA2</italic>
 encodes a master regulator of hematopoiesis that is also linked to endothelial biology. Though the disease-causing mutations commonly occur in the GATA-2 DNA binding domain, we identified a patient with mycobacterial infection and myelodysplasia who had an uncharacterized heterozygous deletion in a <italic>GATA2</italic>
<italic>cis</italic>
-element consisting of an E-box and a GATA motif. Targeted deletion of the equivalent murine element to yield homozygous mutant mice revealed embryonic lethality later than occurred with global <italic>Gata2</italic>
 knockout, hematopoietic stem/progenitor cell depletion, and impaired vascular integrity. Heterozygous mutant mice were viable, but embryos exhibited deficits in definitive, but not primitive, hematopoietic stem/progenitor activity and reduced expression of <italic>Gata2</italic> and its target genes. Mechanistic analysis revealed disruption of the endothelial cell transcriptome and loss of vascular integrity. Thus, the composite element disrupted in a human immunodeficiency is essential for establishment of the murine hematopoietic stem/progenitor cell compartment in the fetal liver and for essential vascular processes.
</p>
</div>
</front>
</TEI>
</record>

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Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity

Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity

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