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J. Biol. Chem., Vol. 282, Issue 22, 16544-16552, June 1, 2007

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-Globin Active Chromatin Hub Formation in Differentiating Erythroid Cells and in p45 NF-E2 Knock-out Mice^*

Jurgen Kooren, Robert-Jan Palstra, Petra Klous, Erik Splinter, Marieke von Lindern, Frank Grosveld, and Wouter de Laat¹

From the Departments of Cell Biology and Genetics and Hematology, Erasmus Medical Center, P. O. Box 2040, 3000 CA Rotterdam, The Netherlands

Expression of the -globin genes proceeds from basal to exceptionally high levels during erythroid differentiation in vivo. High expression is dependent on the locus control region (LCR) and coincides with more frequent LCR-gene contacts. These contacts are established in the context of an active chromatin hub (ACH), a spatial chromatin configuration in which the LCR, together with other regulatory sequences, loops toward the active -globin-like genes. Here, we used recently established I/11 cells as a model system that faithfully recapitulates the in vivo erythroid differentiation program to study the molecular events that accompany and underlie ACH formation. Upon I/11 cell induction, histone modifications changed, the ACH was formed, and the -globin-like genes were transcribed at rates similar to those observed in vivo. The establishment of frequent LCR-gene contacts coincided with a more efficient loading of polymerase onto the -globin promoter. Binding of the transcription factors GATA-1 and EKLF to the locus, although previously shown to be required, was not sufficient for ACH formation. Moreover, we used knock-out mice to show that the erythroid transcription factor p45 NF-E2, which has been implicated in -globin gene regulation, is dispensable for -globin ACH formation.

Received for publication, February 7, 2007 , and in revised form, April 3, 2007.

^* This work was supported by Grants 912-03-009 (to F. G.) and 912-04-082 (to W. d. L.) from the Dutch Scientific Organization (NWO). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

¹ To whom correspondence should be addressed: Dept. of Cell Biology and Genetics, Erasmus Medical Center, P. O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: 31-10-4087164; Fax: 31-10-4089468; E-mail: w.delaat{at}erasmusmc.nl.

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