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Molecular and Cellular Biology, December 2003, p. 8946-8952, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.8946-8952.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Human ß-Globin Locus Control Region HS5 Contains CTCF- and Developmental Stage-Dependent Enhancer-Blocking Activity in Erythroid Cells

Keiji Tanimoto,1* Akiko Sugiura,1 Akane Omori,1 Gary Felsenfeld,2 James Douglas Engel,3 and Akiyoshi Fukamizu1

Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan,1 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0540,2 University of Michigan Medical School, Ann Arbor, Michigan 48109-06163

Received 14 April 2003/ Returned for modification 7 July 2003/ Accepted 10 September 2003

The human ß-globin locus contains five developmentally regulated ß-type globin genes. All five genes depend on the locus control region (LCR), located at the 5' end of the locus, for abundant globin gene transcription. The LCR is composed of five DNase I-hypersensitive sites (HSs), at least a subset of which appear to cooperate to form a holocomplex in activating genes within the locus. We previously tested the requirement for proper LCR polarity by inverting it in human ß-globin yeast artificial chromosome transgenic mice and observed reduced expression of all the ß-type globin genes regardless of developmental stage. This phenotype clearly demonstrated an orientation-dependent activity of the LCR, although the mechanistic basis for the observed activity was obscure. Here, we describe genetic evidence demonstrating that human HS5 includes enhancer-blocking (insulator) activity that is both CTCF and developmental stage dependent. Curiously, we also observed an attenuating activity in HS5 that was specific to the {varepsilon}-globin gene at the primitive stage and was independent of the HS5 CTCF binding site. These observations demonstrate that the phenotype observed in the LCR-inverted locus was in part attributable to placing the HS5 insulator between the LCR HS enhancers (HS1 to HS4) and the promoter of the ß-globin gene.

* Corresponding author. Mailing address: Center for Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki 305-8577, Japan. Phone and fax: 81 (29) 853-6070. E-mail: keiji{at}tara.tsukuba.ac.jp.

Molecular and Cellular Biology, December 2003, p. 8946-8952, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.8946-8952.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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