Endoglin expression in blood and endothelium is differentially regulated by modular assembly of the Ets/Gata hemangioblast code.

2.50
Hdl Handle:
http://hdl.handle.net/10541/68766
Title:
Endoglin expression in blood and endothelium is differentially regulated by modular assembly of the Ets/Gata hemangioblast code.
Authors:
Pimanda, John E; Chan, Wan Y I; Wilson, Nicola K; Smith, Aileen M; Kinston, Sarah; Knezevic, Kathy; Janes, Mary E; Landry, Josette-Renee; Kolb-Kokocinski, Anja; Frampton, Jonathan; Tannahill, David; Ottersbach, Katrin; Follows, George A; Lacaud, Georges; Kouskoff, Valerie; Göttgens, Berthold
Abstract:
Endoglin is an accessory receptor for TGF-beta signaling and is required for normal hemangioblast, early hematopoietic, and vascular development. We have previously shown that an upstream enhancer, Eng -8, together with the promoter region, mediates robust endothelial expression yet is inactive in blood. To identify hematopoietic regulatory elements, we used array-based methods to determine chromatin accessibility across the entire locus. Subsequent transgenic analysis of candidate elements showed that an endothelial enhancer at Eng +9 when combined with an element at Eng +7 functions as a strong hemato-endothelial enhancer. Chromatin immunoprecipitation (ChIP)-chip analysis demonstrated specific binding of Ets factors to the promoter as well as to the -8, +7+9 enhancers in both blood and endothelial cells. By contrast Pu.1, an Ets factor specific to the blood lineage, and Gata2 binding was only detected in blood. Gata2 was bound only at +7 and GATA motifs were required for hematopoietic activity. This modular assembly of regulators gives blood and endothelial cells the regulatory freedom to independently fine-tune gene expression and emphasizes the role of regulatory divergence in driving functional divergence.
Affiliation:
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom. jpimanda@unsw.edu.au
Citation:
Endoglin expression in blood and endothelium is differentially regulated by modular assembly of the Ets/Gata hemangioblast code. 2008, 112 (12):4512-22 Blood
Journal:
Blood
Issue Date:
1-Dec-2008
URI:
http://hdl.handle.net/10541/68766
DOI:
10.1182/blood-2008-05-157560
PubMed ID:
18805961
Type:
Article
Language:
en
ISSN:
1528-0020
Appears in Collections:
All Paterson Institute for Cancer Research; Stem Cell and Haematopoiesis; Stem Cell Biology

Full metadata record

DC FieldValue Language
dc.contributor.authorPimanda, John E-
dc.contributor.authorChan, Wan Y I-
dc.contributor.authorWilson, Nicola K-
dc.contributor.authorSmith, Aileen M-
dc.contributor.authorKinston, Sarah-
dc.contributor.authorKnezevic, Kathy-
dc.contributor.authorJanes, Mary E-
dc.contributor.authorLandry, Josette-Renee-
dc.contributor.authorKolb-Kokocinski, Anja-
dc.contributor.authorFrampton, Jonathan-
dc.contributor.authorTannahill, David-
dc.contributor.authorOttersbach, Katrin-
dc.contributor.authorFollows, George A-
dc.contributor.authorLacaud, Georges-
dc.contributor.authorKouskoff, Valerie-
dc.contributor.authorGöttgens, Berthold-
dc.date.accessioned2009-05-22T13:16:30Z-
dc.date.available2009-05-22T13:16:30Z-
dc.date.issued2008-12-01-
dc.identifier.citationEndoglin expression in blood and endothelium is differentially regulated by modular assembly of the Ets/Gata hemangioblast code. 2008, 112 (12):4512-22 Blooden
dc.identifier.issn1528-0020-
dc.identifier.pmid18805961-
dc.identifier.doi10.1182/blood-2008-05-157560-
dc.identifier.urihttp://hdl.handle.net/10541/68766-
dc.description.abstractEndoglin is an accessory receptor for TGF-beta signaling and is required for normal hemangioblast, early hematopoietic, and vascular development. We have previously shown that an upstream enhancer, Eng -8, together with the promoter region, mediates robust endothelial expression yet is inactive in blood. To identify hematopoietic regulatory elements, we used array-based methods to determine chromatin accessibility across the entire locus. Subsequent transgenic analysis of candidate elements showed that an endothelial enhancer at Eng +9 when combined with an element at Eng +7 functions as a strong hemato-endothelial enhancer. Chromatin immunoprecipitation (ChIP)-chip analysis demonstrated specific binding of Ets factors to the promoter as well as to the -8, +7+9 enhancers in both blood and endothelial cells. By contrast Pu.1, an Ets factor specific to the blood lineage, and Gata2 binding was only detected in blood. Gata2 was bound only at +7 and GATA motifs were required for hematopoietic activity. This modular assembly of regulators gives blood and endothelial cells the regulatory freedom to independently fine-tune gene expression and emphasizes the role of regulatory divergence in driving functional divergence.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshAntigens, CD-
dc.subject.meshBlood-
dc.subject.meshCell Differentiation-
dc.subject.meshCells, Cultured-
dc.subject.meshEmbryo, Mammalian-
dc.subject.meshEmbryonic Development-
dc.subject.meshEndothelium-
dc.subject.meshGATA Transcription Factors-
dc.subject.meshGene Expression Profiling-
dc.subject.meshGene Expression Regulation, Developmental-
dc.subject.meshHemangioblasts-
dc.subject.meshHematopoietic System-
dc.subject.meshHumans-
dc.subject.meshMice-
dc.subject.meshMice, Transgenic-
dc.subject.meshOligonucleotide Array Sequence Analysis-
dc.subject.meshProto-Oncogene Protein c-ets-1-
dc.subject.meshReceptors, Cell Surface-
dc.titleEndoglin expression in blood and endothelium is differentially regulated by modular assembly of the Ets/Gata hemangioblast code.en
dc.typeArticleen
dc.contributor.departmentDepartment of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom. jpimanda@unsw.edu.auen
dc.identifier.journalBlooden

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