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

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 un...

Full description

Saved in:
Bibliographic Details
Published in:Blood Vol. 114; no. 2; p. 299
Main Authors: Hoogenkamp, Maarten, Lichtinger, Monika, Krysinska, Hanna, Lancrin, Christophe, Clarke, Deborah, Williamson, Andrew, Mazzarella, Luca, Ingram, Richard, Jorgensen, Helle, Fisher, Amanda, Tenen, Daniel G, Kouskoff, Valerie, Lacaud, Georges, Bonifer, Constanze
Format: Journal Article
Language:English
Published: United States 09.07.2009
Subjects:
Animals
Blood Cells - metabolism
Cells, Cultured
Chromatin - genetics
Chromatin - metabolism
Core Binding Factor Alpha 2 Subunit - deficiency
Core Binding Factor Alpha 2 Subunit - genetics
Core Binding Factor Alpha 2 Subunit - metabolism
DNA Methylation
Gene Expression Regulation
Mice
Promoter Regions, Genetic - genetics
Protein Binding
RNA, Messenger - genetics
Time Factors
ISSN:1528-0020, 1528-0020
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1528-0020
1528-0020
DOI:10.1182/blood-2008-11-191890