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Molecular and Cellular Biology, November 2007, p. 7425-7438, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00905-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Pu.1 Locus Is Differentially Regulated at the Level of Chromatin Structure and Noncoding Transcription by Alternate Mechanisms at Distinct Developmental Stages of Hematopoiesis{triangledown}

Maarten Hoogenkamp,1 Hanna Krysinska,1 Richard Ingram,1 Gang Huang,2,{dagger} Rachael Barlow,1 Deborah Clarke,1 Alexander Ebralidze,2 Pu Zhang,2 Hiromi Tagoh,1 Peter N. Cockerill,1 Daniel G. Tenen,2 and Constanze Bonifer1*

Section of Experimental Haematology, Leeds Institute of Molecular Medicine, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, United Kingdom,1 Hematology/Oncology Division, Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts 021152

Received 22 May 2007/ Returned for modification 11 June 2007/ Accepted 10 August 2007

The Ets family transcription factor PU.1 is crucial for the regulation of hematopoietic development. Pu.1 is activated in hematopoietic stem cells and is expressed in mast cells, B cells, granulocytes, and macrophages but is switched off in T cells. Many of the transcription factors regulating Pu.1 have been identified, but little is known about how they organize Pu.1 chromatin in development. We analyzed the Pu.1 promoter and the upstream regulatory element (URE) using in vivo footprinting and chromatin immunoprecipitation assays. In B cells, Pu.1 was bound by a set of transcription factors different from that in myeloid cells and adopted alternative chromatin architectures. In T cells, Pu.1 chromatin at the URE was open and the same transcription factor binding sites were occupied as in B cells. The transcription factor RUNX1 was bound to the URE in precursor cells, but binding was down-regulated in maturing cells. In PU.1 knockout precursor cells, the Ets factor Fli-1 compensated for the lack of PU.1, and both proteins could occupy a subset of Pu.1 cis elements in PU.1-expressing cells. In addition, we identified novel URE-derived noncoding transcripts subject to tissue-specific regulation. Our results provide important insights into how overlapping, but different, sets of transcription factors program tissue-specific chromatin structures in the hematopoietic system.

* Corresponding author. Mailing address: University of Leeds, Leeds Institute of Molecular Medicine, St. James's University Hospital, The 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 4 September 2007.

{dagger} Present address: Laboratory of Molecular Aspects of Hematopoiesis, Memorial Sloan-Kettering Cancer Center, Zuckerman Research Center, 408 East 69th St., New York, NY 10021.

Molecular and Cellular Biology, November 2007, p. 7425-7438, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.00905-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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