Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program.

2.50
Hdl Handle:
http://hdl.handle.net/10541/87567
Title:
Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program.
Authors:
Hoogenkamp, Maarten; Lichtinger, Monika; Krysinska, Hanna; Lancrin, Christophe; Clarke, Deborah; Williamson, Andrew J K; Mazzarella, Luca; Ingram, Richard; Jorgensen, Helle; Fisher, Amanda; Tenen, Daniel G; Kouskoff, Valerie; Lacaud, Georges; Bonifer, Constanze
Abstract:
At the cellular level, development progresses through successive regulatory states, each characterized by their specific gene expression profile. However, the molecular mechanisms regulating first the priming and then maintenance of gene expression within one developmental pathway are essentially unknown. The hematopoietic system represents a powerful experimental model to address these questions and here we have focused on a regulatory circuit playing a central role in myelopoiesis: the transcription factor PU.1, its target gene colony-stimulating-factor 1 receptor (Csf1r), and key upstream regulators such as RUNX1. We find that during ontogeny, chromatin unfolding precedes the establishment of active histone marks and the formation of stable transcription factor complexes at the Pu.1 locus and we show that chromatin remodeling is mediated by the transient binding of RUNX1 to Pu.1 cis-elements. By contrast, chromatin reorganization of Csf1r requires prior expression of PU.1 together with RUNX1 binding. Once the full hematopoietic program is established, stable transcription factor complexes and active chromatin can be maintained without RUNX1. Our experiments therefore demonstrate how individual transcription factors function in a differentiation stage-specific manner to differentially affect the initiation versus maintenance of a developmental program.
Affiliation:
Leeds Institute for Molecular Medicine, University of Leeds, Leeds, United Kingdom.
Citation:
Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program. 2009, 114 (2):299-309 Blood
Journal:
Blood
Issue Date:
9-Jul-2009
URI:
http://hdl.handle.net/10541/87567
DOI:
10.1182/blood-2008-11-191890
PubMed ID:
19339695
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.authorHoogenkamp, Maartenen
dc.contributor.authorLichtinger, Monikaen
dc.contributor.authorKrysinska, Hannaen
dc.contributor.authorLancrin, Christopheen
dc.contributor.authorClarke, Deborahen
dc.contributor.authorWilliamson, Andrew J Ken
dc.contributor.authorMazzarella, Lucaen
dc.contributor.authorIngram, Richarden
dc.contributor.authorJorgensen, Helleen
dc.contributor.authorFisher, Amandaen
dc.contributor.authorTenen, Daniel Gen
dc.contributor.authorKouskoff, Valerieen
dc.contributor.authorLacaud, Georgesen
dc.contributor.authorBonifer, Constanzeen
dc.date.accessioned2009-12-08T12:26:01Z-
dc.date.available2009-12-08T12:26:01Z-
dc.date.issued2009-07-09-
dc.identifier.citationEarly chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program. 2009, 114 (2):299-309 Blooden
dc.identifier.issn1528-0020-
dc.identifier.pmid19339695-
dc.identifier.doi10.1182/blood-2008-11-191890-
dc.identifier.urihttp://hdl.handle.net/10541/87567-
dc.description.abstractAt the cellular level, development progresses through successive regulatory states, each characterized by their specific gene expression profile. However, the molecular mechanisms regulating first the priming and then maintenance of gene expression within one developmental pathway are essentially unknown. The hematopoietic system represents a powerful experimental model to address these questions and here we have focused on a regulatory circuit playing a central role in myelopoiesis: the transcription factor PU.1, its target gene colony-stimulating-factor 1 receptor (Csf1r), and key upstream regulators such as RUNX1. We find that during ontogeny, chromatin unfolding precedes the establishment of active histone marks and the formation of stable transcription factor complexes at the Pu.1 locus and we show that chromatin remodeling is mediated by the transient binding of RUNX1 to Pu.1 cis-elements. By contrast, chromatin reorganization of Csf1r requires prior expression of PU.1 together with RUNX1 binding. Once the full hematopoietic program is established, stable transcription factor complexes and active chromatin can be maintained without RUNX1. Our experiments therefore demonstrate how individual transcription factors function in a differentiation stage-specific manner to differentially affect the initiation versus maintenance of a developmental program.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshBlood Cells-
dc.subject.meshCells, Cultured-
dc.subject.meshChromatin-
dc.subject.meshCore Binding Factor Alpha 2 Subunit-
dc.subject.meshDNA Methylation-
dc.subject.meshGene Expression Regulation-
dc.subject.meshMice-
dc.subject.meshPromoter Regions, Genetic-
dc.subject.meshProtein Binding-
dc.subject.meshRNA, Messenger-
dc.subject.meshTime Factors-
dc.titleEarly chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program.en
dc.typeArticleen
dc.contributor.departmentLeeds Institute for Molecular Medicine, University of Leeds, Leeds, United Kingdom.en
dc.identifier.journalBlooden

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