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J. Biol. Chem., Vol. 281, Issue 41, 30573-30580, October 13, 2006

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Enhancer Blocking by Chicken -Globin 5'-HS4

ROLE OF ENHANCER STRENGTH AND INSULATOR NUCLEOSOME DEPLETION^*

Hui Zhao¹, AeRi Kim, Sang-hyun Song, and Ann Dean²

From the Laboratory of Cellular and Developmental Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892 and the Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan 609-735 Korea

The 5'-HS4 chicken -globin insulator functions as a positional enhancer blocker on chromatinized episomes in human cells, blocking the HS2 enhancer of the human -globin locus control region from activating a downstream -globin gene. 5'-HS4 interrupted formation of a domain of histone H3 and H4 acetylation encompassing the 6-kb minilocus and inhibited transfer of RNA polymerase from the enhancer to the gene promoter. We found that the enhancer blocking phenotype was amplified when the insulated locus contained a weakened HS2 enhancer in which clustered point mutations eliminated interaction of the transcription factor GATA-1. The GATA-1 mutation compromised recruitment of histone acetyltransferases and RNA polymerase II to HS2. Enhancer blocking correlated with a significant depletion of nucleosomes in the core region of the insulator as revealed by micrococcal nuclease and DNase I digestion studies. Nucleosome depletion at 5'-HS4 was dependent on interaction of the insulator protein CCCTC-binding factor (CTCF) and was required for enhancer blocking. These findings provide evidence that a domain of active chromatin is formed by spreading from an enhancer to a target gene and can be blocked by a nucleosome-free gap in an insulator.

Received for publication, July 17, 2006

^* This work was supported by a grant from the Intramural Program of the NIDDK, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, Seattle, WA 98109.

² To whom correspondence should be addressed: NIDDK, National Institutes of Health, Bldg. 50, Rm. 3154, 50 South Dr., MSC 8028, Bethesda, MD 20892. Tel.: 301-496-6068; Fax: 301-496-5239; E-mail: anndean{at}helix.nih.gov.

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