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Molecular and Cellular Biology, November 2003, p. 8099-8109, Vol. 23, No. 22
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.22.8099-8109.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Human Globin Enhancer Causes both Discrete and Widespread Alterations in Chromatin Structure

AeRi Kim and Ann Dean*

Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Received 23 May 2003/ Returned for modification 10 July 2003/ Accepted 30 July 2003

Gene activation requires alteration of chromatin structure to facilitate active transcription complex formation at a gene promoter. Nucleosome remodeling complexes and histone modifying complexes each play unique and interdependent roles in bringing about these changes. The role of distant enhancers in these structural alterations is not well understood. We studied nucleosome remodeling and covalent histone modification mediated by the ß-globin locus control region HS2 enhancer at nucleosome-level resolution throughout a 5.5-kb globin gene model locus in vivo in K562 cells. We compared the transcriptionally active locus to one in which HS2 was inactivated by mutations in the core NF-E2 sites. In contrast to inactive templates, nucleosomes were mobilized in discrete areas of the active locus, including the HS2 core and the proximal promoter. Large differences in restriction enzyme accessibility between the active and inactive templates were limited to the regions of nucleosome mobilization, which subsumed the DNase I hypersensitive sites. In contrast to this discrete pattern, histone H3 and H4 acetylation and H3 K4 methylation were elevated across the entire active locus, accompanied by depletion of linker histone H1. The coding region of the gene differed from the regulatory regions, demonstrating both nucleosome mobilization and histone hyperacetylation, but lacked differences in restriction enzyme accessibility between transcriptionally active and inactive genes. Thus, although the histone modification pattern we observe is consistent with the spreading of histone modifying activity from the distant enhancer, the pattern of nucleosome mobilization is more compatible with direct contact between an enhancer and promoter.

* Corresponding author. Mailing address: Laboratory of Cellular and Developmental Biology, NIDDK, NIH, Building 50, Room 3154, 50 South Dr., MSC 8028, Bethesda, MD 20892-8028. Phone: (301) 496-6068. Fax: (301) 496-5239. E-mail: anndean{at}helix.nih.gov.

Molecular and Cellular Biology, November 2003, p. 8099-8109, Vol. 23, No. 22
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.22.8099-8109.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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