The paralogous hematopoietic regulators Lyl1 and Scl are coregulated by Ets and GATA factors, but Lyl1 cannot rescue the early Scl-/- phenotype.

2.50
Hdl Handle:
http://hdl.handle.net/10541/70325
Title:
The paralogous hematopoietic regulators Lyl1 and Scl are coregulated by Ets and GATA factors, but Lyl1 cannot rescue the early Scl-/- phenotype.
Authors:
Chan, Wan Y I; Follows, George A; Lacaud, Georges; Pimanda, John E; Landry, Josette-Renee; Kinston, Sarah; Knezevic, Kathy; Piltz, Sandie; Donaldson, Ian J; Gambardella, Laure; Sablitzky, Fred; Green, Anthony R; Kouskoff, Valerie; Göttgens, Berthold
Abstract:
Transcription factors are key regulators of hematopoietic stem cells (HSCs), yet the molecular mechanisms that control their expression are largely unknown. Previously, we demonstrated that expression of Scl/Tal1, a transcription factor required for the specification of HSCs, is controlled by Ets and GATA factors. Here we characterize the molecular mechanisms controlling expression of Lyl1, a paralog of Scl also required for HSC function. Two closely spaced promoters directed expression to hematopoietic progenitor, megakaryocytic, and endothelial cells in transgenic mice. Conserved binding sites required for promoter activity were bound in vivo by GATA-2 and the Ets factors Fli1, Elf1, Erg, and PU.1. However, despite coregulation of Scl and Lyl1 by the same Ets and GATA factors, Scl expression was initiated prior to Lyl1 in embryonic stem (ES) cell differentiation assays. Moreover, ectopic expression of Scl but not Lyl1 rescued hematopoietic differentiation in Scl-/- ES cells, thus providing a molecular explanation for the vastly different phenotypes of Scl-/- and Lyl1-/- mouse embryos. Furthermore, coregulation of Scl and Lyl1 later during development may explain the mild phenotype of Scl-/- adult HSCs.
Affiliation:
Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, United Kingdom.
Citation:
The paralogous hematopoietic regulators Lyl1 and Scl are coregulated by Ets and GATA factors, but Lyl1 cannot rescue the early Scl-/- phenotype. 2007, 109 (5):1908-16 Blood
Journal:
Blood
Issue Date:
1-Mar-2007
URI:
http://hdl.handle.net/10541/70325
DOI:
10.1182/blood-2006-05-023226
PubMed ID:
17053063
Type:
Article
Language:
en
ISSN:
0006-4971
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorChan, Wan Y I-
dc.contributor.authorFollows, George A-
dc.contributor.authorLacaud, Georges-
dc.contributor.authorPimanda, John E-
dc.contributor.authorLandry, Josette-Renee-
dc.contributor.authorKinston, Sarah-
dc.contributor.authorKnezevic, Kathy-
dc.contributor.authorPiltz, Sandie-
dc.contributor.authorDonaldson, Ian J-
dc.contributor.authorGambardella, Laure-
dc.contributor.authorSablitzky, Fred-
dc.contributor.authorGreen, Anthony R-
dc.contributor.authorKouskoff, Valerie-
dc.contributor.authorGöttgens, Berthold-
dc.date.accessioned2009-06-12T13:54:28Z-
dc.date.available2009-06-12T13:54:28Z-
dc.date.issued2007-03-01-
dc.identifier.citationThe paralogous hematopoietic regulators Lyl1 and Scl are coregulated by Ets and GATA factors, but Lyl1 cannot rescue the early Scl-/- phenotype. 2007, 109 (5):1908-16 Blooden
dc.identifier.issn0006-4971-
dc.identifier.pmid17053063-
dc.identifier.doi10.1182/blood-2006-05-023226-
dc.identifier.urihttp://hdl.handle.net/10541/70325-
dc.description.abstractTranscription factors are key regulators of hematopoietic stem cells (HSCs), yet the molecular mechanisms that control their expression are largely unknown. Previously, we demonstrated that expression of Scl/Tal1, a transcription factor required for the specification of HSCs, is controlled by Ets and GATA factors. Here we characterize the molecular mechanisms controlling expression of Lyl1, a paralog of Scl also required for HSC function. Two closely spaced promoters directed expression to hematopoietic progenitor, megakaryocytic, and endothelial cells in transgenic mice. Conserved binding sites required for promoter activity were bound in vivo by GATA-2 and the Ets factors Fli1, Elf1, Erg, and PU.1. However, despite coregulation of Scl and Lyl1 by the same Ets and GATA factors, Scl expression was initiated prior to Lyl1 in embryonic stem (ES) cell differentiation assays. Moreover, ectopic expression of Scl but not Lyl1 rescued hematopoietic differentiation in Scl-/- ES cells, thus providing a molecular explanation for the vastly different phenotypes of Scl-/- and Lyl1-/- mouse embryos. Furthermore, coregulation of Scl and Lyl1 later during development may explain the mild phenotype of Scl-/- adult HSCs.en
dc.language.isoenen
dc.subjectCancer Proteinsen
dc.subject.meshAmino Acid Sequence-
dc.subject.meshAnimals-
dc.subject.meshBase Sequence-
dc.subject.meshBasic Helix-Loop-Helix Transcription Factors-
dc.subject.meshCell Line-
dc.subject.meshConserved Sequence-
dc.subject.meshEmbryo, Mammalian-
dc.subject.meshEndothelial Cells-
dc.subject.meshGATA2 Transcription Factor-
dc.subject.meshGene Expression-
dc.subject.meshHematopoiesis-
dc.subject.meshHumans-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshNeoplasm Proteins-
dc.subject.meshPhenotype-
dc.subject.meshPromoter Regions, Genetic-
dc.subject.meshProto-Oncogene Protein c-ets-1-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshSequence Alignment-
dc.subject.meshTime Factors-
dc.titleThe paralogous hematopoietic regulators Lyl1 and Scl are coregulated by Ets and GATA factors, but Lyl1 cannot rescue the early Scl-/- phenotype.en
dc.typeArticleen
dc.contributor.departmentDepartment of Haematology, Cambridge Institute for Medical Research, University of Cambridge, United Kingdom.en
dc.identifier.journalBlooden

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