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A Complex Chromatin Landscape Revealed by Patterns of Nuclease Sensitivity and Histone Modification within the Mouse ß-Globin Locus

Michael Bulger,¹ Dirk Schübeler,^1, M. A. Bender,¹ Joan Hamilton,¹ Catherine M. Farrell,² Ross C. Hardison,³ and Mark Groudine^1,4*

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,¹ National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892,² Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802,³ Department of Radiation Oncology, University of Washington School of Medicine, Seattle, Washington 98195⁴

Received 14 February 2003/ Returned for modification 27 March 2003/ Accepted 13 May 2003

In order to create an extended map of chromatin features within a mammalian multigene locus, we have determined the extent of nuclease sensitivity and the pattern of histone modifications associated with the mouse ß-globin genes in adult erythroid tissue. We show that the nuclease-sensitive domain encompasses the ß-globin genes along with several flanking olfactory receptor genes that are inactive in erythroid cells. We describe enhancer-blocking or boundary elements on either side of the locus that are bound in vivo by the transcription factor CTCF, but we found that they do not coincide with transitions in nuclease sensitivity flanking the locus or with patterns of histone modifications within it. In addition, histone hyperacetylation and dimethylation of histone H3 K4 are not uniform features of the nuclease-sensitive mouse ß-globin domain but rather define distinct subdomains within it. Our results reveal a complex chromatin landscape for the active ß-globin locus and illustrate the complexity of broad structural changes that accompany gene activation.

Present address: Friedrich Miescher Institute for Biomedical Research, CH-4058 Basel, Switzerland.

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