LymphedemaV1, Pmc, Corpus, bibRecord, 002F18

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

Identifieur interne : 002F18 ( Pmc/Corpus ); précédent : 002F17; suivant : 002F19

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

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

Source :

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

RBID : PMC:3461907

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

Links to Exploration step

PMC:3461907

Le document en format XML

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-element mutated in <italic>GATA2</italic>-dependent immunodeficiency governs hematopoiesis and vascular integrity
</title>
<author><name sortKey="Johnson, Kirby D" sort="Johnson, Kirby D" uniqKey="Johnson K" first="Kirby D." last="Johnson">Kirby D. Johnson</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Hsu, Amy P" sort="Hsu, Amy P" uniqKey="Hsu A" first="Amy P." last="Hsu">Amy P. Hsu</name>
<affiliation><nlm:aff id="JCI61623">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ryu, Myung Jeom" sort="Ryu, Myung Jeom" uniqKey="Ryu M" first="Myung-Jeom" last="Ryu">Myung-Jeom Ryu</name>
<affiliation><nlm:aff id="JCI61623">McArdle Laboratory for Cancer Research, Madison, Wisconsin, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wang, Jinyong" sort="Wang, Jinyong" uniqKey="Wang J" first="Jinyong" last="Wang">Jinyong Wang</name>
<affiliation><nlm:aff id="JCI61623">McArdle Laboratory for Cancer Research, Madison, Wisconsin, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gao, Xin" sort="Gao, Xin" uniqKey="Gao X" first="Xin" last="Gao">Xin Gao</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Boyer, Meghan E" sort="Boyer, Meghan E" uniqKey="Boyer M" first="Meghan E." last="Boyer">Meghan E. Boyer</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Liu, Yangang" sort="Liu, Yangang" uniqKey="Liu Y" first="Yangang" last="Liu">Yangang Liu</name>
<affiliation><nlm:aff id="JCI61623">McArdle Laboratory for Cancer Research, Madison, Wisconsin, USA.</nlm:aff>
</affiliation>
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<author><name sortKey="Lee, Youngsook" sort="Lee, Youngsook" uniqKey="Lee Y" first="Youngsook" last="Lee">Youngsook Lee</name>
<affiliation><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>
</affiliation>
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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>
<affiliation><nlm:aff id="JCI61623">Hematology Section, Department of Laboratory Medicine, NIH Clinical Center, Bethesda, Maryland, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Keles, Sunduz" sort="Keles, Sunduz" uniqKey="Keles S" first="Sunduz" last="Keles">Sunduz Keles</name>
<affiliation><nlm:aff id="JCI61623">Departments of Biostatistics and Medical Informatics and Statistics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zhang, Jing" sort="Zhang, Jing" uniqKey="Zhang J" first="Jing" last="Zhang">Jing Zhang</name>
<affiliation><nlm:aff id="JCI61623">McArdle Laboratory for Cancer Research, Madison, Wisconsin, USA.</nlm:aff>
</affiliation>
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<author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M." last="Holland">Steven M. Holland</name>
<affiliation><nlm:aff id="JCI61623">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bresnick, Emery H" sort="Bresnick, Emery H" uniqKey="Bresnick E" first="Emery H." last="Bresnick">Emery H. Bresnick</name>
<affiliation><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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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main"><italic>Cis</italic>
-element mutated in <italic>GATA2</italic>-dependent immunodeficiency governs hematopoiesis and vascular integrity
</title>
<author><name sortKey="Johnson, Kirby D" sort="Johnson, Kirby D" uniqKey="Johnson K" first="Kirby D." last="Johnson">Kirby D. Johnson</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Hsu, Amy P" sort="Hsu, Amy P" uniqKey="Hsu A" first="Amy P." last="Hsu">Amy P. Hsu</name>
<affiliation><nlm:aff id="JCI61623">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Ryu, Myung Jeom" sort="Ryu, Myung Jeom" uniqKey="Ryu M" first="Myung-Jeom" last="Ryu">Myung-Jeom Ryu</name>
<affiliation><nlm:aff id="JCI61623">McArdle Laboratory for Cancer Research, Madison, Wisconsin, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Wang, Jinyong" sort="Wang, Jinyong" uniqKey="Wang J" first="Jinyong" last="Wang">Jinyong Wang</name>
<affiliation><nlm:aff id="JCI61623">McArdle Laboratory for Cancer Research, Madison, Wisconsin, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Gao, Xin" sort="Gao, Xin" uniqKey="Gao X" first="Xin" last="Gao">Xin Gao</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Boyer, Meghan E" sort="Boyer, Meghan E" uniqKey="Boyer M" first="Meghan E." last="Boyer">Meghan E. Boyer</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Liu, Yangang" sort="Liu, Yangang" uniqKey="Liu Y" first="Yangang" last="Liu">Yangang Liu</name>
<affiliation><nlm:aff id="JCI61623">McArdle Laboratory for Cancer Research, Madison, Wisconsin, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Lee, Youngsook" sort="Lee, Youngsook" uniqKey="Lee Y" first="Youngsook" last="Lee">Youngsook Lee</name>
<affiliation><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>
</affiliation>
</author>
<author><name sortKey="Calvo, Katherine R" sort="Calvo, Katherine R" uniqKey="Calvo K" first="Katherine R." last="Calvo">Katherine R. Calvo</name>
<affiliation><nlm:aff id="JCI61623">Hematology Section, Department of Laboratory Medicine, NIH Clinical Center, Bethesda, Maryland, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Keles, Sunduz" sort="Keles, Sunduz" uniqKey="Keles S" first="Sunduz" last="Keles">Sunduz Keles</name>
<affiliation><nlm:aff id="JCI61623">Departments of Biostatistics and Medical Informatics and Statistics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Zhang, Jing" sort="Zhang, Jing" uniqKey="Zhang J" first="Jing" last="Zhang">Jing Zhang</name>
<affiliation><nlm:aff id="JCI61623">McArdle Laboratory for Cancer Research, Madison, Wisconsin, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Holland, Steven M" sort="Holland, Steven M" uniqKey="Holland S" first="Steven M." last="Holland">Steven M. Holland</name>
<affiliation><nlm:aff id="JCI61623">Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bresnick, Emery H" sort="Bresnick, Emery H" uniqKey="Bresnick E" first="Emery H." last="Bresnick">Emery H. Bresnick</name>
<affiliation><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>
</affiliation>
</author>
</analytic>
<series><title level="j">The Journal of Clinical Investigation</title>
<idno type="ISSN">0021-9738</idno>
<idno type="eISSN">1558-8238</idno>
<imprint><date when="2012">2012</date>
</imprint>
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<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>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
  <front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Invest</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Clin. Invest</journal-id>
<journal-id journal-id-type="publisher-id">J CLIN INVEST</journal-id>
<journal-title-group><journal-title>The Journal of Clinical Investigation</journal-title>
</journal-title-group>
<issn pub-type="ppub">0021-9738</issn>
<issn pub-type="epub">1558-8238</issn>
<publisher><publisher-name>American Society for Clinical Investigation</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">22996659</article-id>
<article-id pub-id-type="pmc">3461907</article-id>
<article-id pub-id-type="publisher-id">61623</article-id>
<article-id pub-id-type="doi">10.1172/JCI61623</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title><italic>Cis</italic>
-element mutated in <italic>GATA2</italic>-dependent immunodeficiency governs hematopoiesis and vascular integrity
</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Johnson</surname>
<given-names>Kirby D.</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hsu</surname>
<given-names>Amy P.</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ryu</surname>
<given-names>Myung-Jeom</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Wang</surname>
<given-names>Jinyong</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gao</surname>
<given-names>Xin</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Boyer</surname>
<given-names>Meghan E.</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Yangang</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lee</surname>
<given-names>Youngsook</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Calvo</surname>
<given-names>Katherine R.</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Keles</surname>
<given-names>Sunduz</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Jing</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Holland</surname>
<given-names>Steven M.</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bresnick</surname>
<given-names>Emery H.</given-names>
</name>
<xref ref-type="aff" rid="JCI61623">1</xref>
</contrib>
</contrib-group>
<aff id="JCI61623"><label>1</label>
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.<label>2</label>
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.<label>3</label>
McArdle Laboratory for Cancer Research, Madison, Wisconsin, USA.<label>4</label>
Hematology Section, Department of Laboratory Medicine, NIH Clinical Center, Bethesda, Maryland, USA.<label>5</label>
Departments of Biostatistics and Medical Informatics and Statistics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.</aff>
<author-notes><corresp>Address correspondence to: Emery H. Bresnick, University of Wisconsin School of Medicine and Public Health, UW Carbone Cancer Center, 4009 Wisconsin Institutes for Medical Research, 1111 Highland Avenue, Madison, Wisconsin 53705, USA. Phone: 608.265.6446; Fax: 608.262.4598; E-mail:
<email>ehbresni@wisc.edu</email>. Or to: Steven Holland, NIH, NIAID, Laboratory of Clinical Infectious Diseases, CRC B3-4141, MSC 1684, Bethesda, Maryland 20892, USA. Phone: 301.451.9019; Fax: 301.480.4507; E-mail:
<email>SHOLLAND@niaid.nih.gov</email>. Or to: Jing Zhang, University of Wisconsin School of Medicine and Public Health, 417a McArdle Laboratory for Cancer Research, 1400 University Avenue, Madison, Wisconsin 53706, USA. Phone: 608.263.1147; Fax: 608.262.2824; E-mail:
<email>zhang@oncology.wisc.edu</email>.
</corresp>
<fn><p><bold>Authorship note:</bold> Kirby D. Johnson, Amy P. Hsu, and Myung-Jeom Ryu contributed equally to this work.
</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>10</day>
<month>9</month>
<year>2012</year>
</pub-date>
<pub-date pub-type="ppub"><day>1</day>
<month>10</month>
<year>2012</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>10</day>
<month>9</month>
<year>2012</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on the 
 							. </pmc-comment>
      <volume>122</volume>
<issue>10</issue>
<fpage>3692</fpage>
<lpage>3704</lpage>
<history><date date-type="received"><day>25</day>
<month>10</month>
<year>2011</year>
</date>
<date date-type="accepted"><day>19</day>
<month>7</month>
<year>2012</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2012, American Society for Clinical Investigation</copyright-statement>
<copyright-year>2012</copyright-year>
</permissions>
<abstract><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>
</abstract>
</article-meta>
</front>
</pmc>
</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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Abstract

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