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Molecular and Cellular Biology, February 2003, p. 1460-1469, Vol. 23, No. 4
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.4.1460-1469.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Maintenance of Open Chromatin and Selective Genomic Occupancy at the Cell Cycle-Regulated Histone H4 Promoter during Differentiation of HL-60 Promyelocytic Leukemia Cells

Hayk Hovhannisyan,1 Brian Cho,1 Partha Mitra,1 Martin Montecino,2 Gary S. Stein,1 Andre J. van Wijnen,1 and Janet L. Stein1*

Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655,1 Departamento de Biologia Molecular, Universidad de Concepcion, Concepcion, Chile2

Received 5 August 2002/ Returned for modification 24 September 2002/ Accepted 12 November 2002

During the shutdown of proliferation and onset of differentiation of HL-60 promyelocytic leukemia cells, expression of the cell cycle-dependent histone genes is downregulated at the level of transcription. To address the mechanism by which this regulation occurs, we examined the chromatin structure of the histone H4/n (FO108, H4FN) gene locus. Micrococcal nuclease, DNase I, and restriction enzymes show similar cleavage sites and levels of sensitivity at the H4/n locus in both proliferating and differentiated HL-60 cells. In contrast, differentiation-related activation of the cyclin-dependent kinase inhibitor p21cip1/WAF1 gene is accompanied by increased nuclease hypersensitivity. Chromatin immunoprecipitation assays of the H4/n gene reveal that acetylated histones H3 and H4 are maintained at the same levels in proliferating and postproliferative cells. Thus, the chromatin of the H4/n locus remains in an open state even after transcription ceases. Using ligation-mediated PCR to visualize genomic DNase I footprints at single-nucleotide resolution, we find that protein occupancy at the site II cell cycle element is selectively diminished in differentiated cells while the site I element remains occupied. Decreased occupancy of site II is reflected by loss of the site II binding protein HiNF-P. We conclude that H4 gene transcription during differentiation is downregulated by modulating protein interaction at the site II cell cycle element and that retention of an open chromatin conformation may be associated with site I occupancy.

* Corresponding author. Mailing address: Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655. Phone: (508) 856-5625. Fax: (508) 856-6800. E-mail: janet.stein{at}umassmed.edu.

Molecular and Cellular Biology, February 2003, p. 1460-1469, Vol. 23, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.4.1460-1469.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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