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Molecular and Cellular Biology, February 2007, p. 878-887, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01915-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Two-Step, PU.1-Dependent Mechanism for Developmentally Regulated Chromatin Remodeling and Transcription of the c-fms Gene{triangledown}

Hanna Krysinska,1 Maarten Hoogenkamp,1 Richard Ingram,1 Nicola Wilson,1 Hiromi Tagoh,1 Peter Laslo,2 Harinder Singh,2 and Constanze Bonifer1*

University of Leeds, Division of Experimental Haematology, Leeds Institute for Molecular Medicine, St. James's University Hospital, Leeds LS9 7TF, United Kingdom,1 Howard Hughes Medical Institute and Department of Molecular Genetics and Cell Biology, The University of Chicago, CIS 929 E. 57th St., Chicago, Illinois 606372

Received 10 October 2006/ Returned for modification 7 November 2006/ Accepted 10 November 2006

Hematopoietic stem cells and multipotent progenitors exhibit low-level transcription and partial chromatin reorganization of myeloid cell-specific genes including the c-fms (csf1R) locus. Expression of the c-fms gene is dependent on the Ets family transcription factor PU.1 and is upregulated during myeloid differentiation, enabling committed macrophage precursors to respond to colony-stimulating factor 1. To analyze molecular mechanisms underlying the transcriptional priming and developmental upregulation of the c-fms gene, we have utilized myeloid progenitors lacking the transcription factor PU.1. PU.1 can bind to sites in both the c-fms promoter and the c-fms intronic regulatory element (FIRE enhancer). Unlike wild-type progenitors, the PU.1–/– cells are unable to express c-fms or initiate macrophage differentiation. When PU.1 was reexpressed in mutant progenitors, the chromatin structure of the c-fms promoter was rapidly reorganized. In contrast, assembly of transcription factors at FIRE, acquisition of active histone marks, and high levels of c-fms transcription occurred with significantly slower kinetics. We demonstrate that the reason for this differential activation was that PU.1 was required to promote induction and binding of a secondary transcription factor, Egr-2, which is important for FIRE enhancer activity. These data suggest that the c-fms promoter is maintained in a primed state by PU.1 in progenitor cells and that at FIRE PU.1 functions with another transcription factor to direct full activation of the c-fms locus in differentiated myeloid cells. The two-step mechanism of developmental gene activation that we describe here may be utilized to regulate gene activity in a variety of developmental pathways.

* Corresponding author. Mailing address: University of Leeds, Leeds Institute of Molecular Medicine, St. James's University Hospital, Wellcome Trust Brenner Building, Leeds LS9 7TF, United Kingdom. Phone: 44-113-3438525. Fax: 44-113-3438502. E-mail: c.bonifer{at}leeds.ac.uk.

{triangledown} Published ahead of print on 20 November 2006.

Molecular and Cellular Biology, February 2007, p. 878-887, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.01915-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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