Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors.

2.50
Hdl Handle:
http://hdl.handle.net/10541/85222
Title:
Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors.
Authors:
Landry, Josette-Renee; Bonadies, Nicolas; Kinston, Sarah; Knezevic, Kathy; Wilson, Nicola K; Oram, S Helen; Janes, Mary E; Piltz, Sandie; Hammett, Michelle; Carter, Jacinta; Hamilton, Tina; Donaldson, Ian J; Lacaud, Georges; Frampton, Jonathan; Follows, George A; Kouskoff, Valerie; Göttgens, Berthold
Abstract:
The Lmo2 gene encodes a transcriptional cofactor critical for the development of hematopoietic stem cells. Ectopic LMO2 expression causes leukemia in T-cell acute lymphoblastic leukemia (T-ALL) patients and severe combined immunodeficiency patients undergoing retroviral gene therapy. Tightly controlled Lmo2 expression is therefore essential, yet no comprehensive analysis of Lmo2 regulation has been published so far. By comparative genomics, we identified 17 highly conserved noncoding elements, 9 of which revealed specific acetylation marks in chromatin-immunoprecipitation and microarray (ChIP-chip) assays performed across 250 kb of the Lmo2 locus in 11 cell types covering different stages of hematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers, which together recapitulated the full expression pattern of Lmo2, directing expression to endothelium, hematopoietic cells, tail, and forebrain. Interestingly, distinct combinations of specific distal regulatory elements were required to extend endothelial activity of the LMO2 promoter to yolk sac or fetal liver hematopoietic cells. Finally, Sfpi1/Pu.1, Fli1, Gata2, Tal1/Scl, and Lmo2 were shown to bind to and transactivate Lmo2 hematopoietic enhancers, thus identifying key upstream regulators and positioning Lmo2 within hematopoietic regulatory networks.
Affiliation:
Department of Haematology, Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom.
Citation:
Expression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors. 2009, 113 (23):5783-92 Blood
Journal:
Blood
Issue Date:
4-Jun-2009
URI:
http://hdl.handle.net/10541/85222
DOI:
10.1182/blood-2008-11-187757
PubMed ID:
19171877
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.authorLandry, Josette-Reneeen
dc.contributor.authorBonadies, Nicolasen
dc.contributor.authorKinston, Sarahen
dc.contributor.authorKnezevic, Kathyen
dc.contributor.authorWilson, Nicola Ken
dc.contributor.authorOram, S Helenen
dc.contributor.authorJanes, Mary Een
dc.contributor.authorPiltz, Sandieen
dc.contributor.authorHammett, Michelleen
dc.contributor.authorCarter, Jacintaen
dc.contributor.authorHamilton, Tinaen
dc.contributor.authorDonaldson, Ian Jen
dc.contributor.authorLacaud, Georgesen
dc.contributor.authorFrampton, Jonathanen
dc.contributor.authorFollows, George Aen
dc.contributor.authorKouskoff, Valerieen
dc.contributor.authorGöttgens, Bertholden
dc.date.accessioned2009-11-03T13:06:18Z-
dc.date.available2009-11-03T13:06:18Z-
dc.date.issued2009-06-04-
dc.identifier.citationExpression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors. 2009, 113 (23):5783-92 Blooden
dc.identifier.issn1528-0020-
dc.identifier.pmid19171877-
dc.identifier.doi10.1182/blood-2008-11-187757-
dc.identifier.urihttp://hdl.handle.net/10541/85222-
dc.description.abstractThe Lmo2 gene encodes a transcriptional cofactor critical for the development of hematopoietic stem cells. Ectopic LMO2 expression causes leukemia in T-cell acute lymphoblastic leukemia (T-ALL) patients and severe combined immunodeficiency patients undergoing retroviral gene therapy. Tightly controlled Lmo2 expression is therefore essential, yet no comprehensive analysis of Lmo2 regulation has been published so far. By comparative genomics, we identified 17 highly conserved noncoding elements, 9 of which revealed specific acetylation marks in chromatin-immunoprecipitation and microarray (ChIP-chip) assays performed across 250 kb of the Lmo2 locus in 11 cell types covering different stages of hematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers, which together recapitulated the full expression pattern of Lmo2, directing expression to endothelium, hematopoietic cells, tail, and forebrain. Interestingly, distinct combinations of specific distal regulatory elements were required to extend endothelial activity of the LMO2 promoter to yolk sac or fetal liver hematopoietic cells. Finally, Sfpi1/Pu.1, Fli1, Gata2, Tal1/Scl, and Lmo2 were shown to bind to and transactivate Lmo2 hematopoietic enhancers, thus identifying key upstream regulators and positioning Lmo2 within hematopoietic regulatory networks.en
dc.language.isoenen
dc.subjectLeukaemiaen
dc.subject.meshAnimals-
dc.subject.meshBasic Helix-Loop-Helix Transcription Factors-
dc.subject.meshCell Line-
dc.subject.meshChromatin Immunoprecipitation-
dc.subject.meshDNA-Binding Proteins-
dc.subject.meshEmbryo, Mammalian-
dc.subject.meshGATA Transcription Factors-
dc.subject.meshGene Expression Regulation, Developmental-
dc.subject.meshGenome-
dc.subject.meshLeukemia-
dc.subject.meshMetalloproteins-
dc.subject.meshMice-
dc.subject.meshProtein Binding-
dc.subject.meshProto-Oncogene Proteins-
dc.subject.meshTelomerase-
dc.subject.meshTissue Array Analysis-
dc.subject.meshTrans-Activators-
dc.titleExpression of the leukemia oncogene Lmo2 is controlled by an array of tissue-specific elements dispersed over 100 kb and bound by Tal1/Lmo2, Ets, and Gata factors.en
dc.typeArticleen
dc.contributor.departmentDepartment of Haematology, Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom.en
dc.identifier.journalBlooden

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