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Molecular and Cellular Biology, October 2000, p. 7572-7582, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

An Ikaros-Containing Chromatin-Remodeling Complex in Adult-Type Erythroid Cells

David W. O'Neill,1 Stuti S. Schoetz,2 Rocio A. Lopez,2 Madalyn Castle,2 Lisa Rabinowitz,2 Erika Shor,2 Dayana Krawchuk,2 Mary G. Goll,2 Manfred Renz,3 Hans-Peter Seelig,3 Sunmi Han,4 Rho H. Seong,4 Sang D. Park,4 Theodora Agalioti,5 Nikhil Munshi,5 Dimitrios Thanos,5 Hediye Erdjument-Bromage,6 Paul Tempst,6 and Arthur Bank2,7,*

Departments of Pathology,1 Genetics and Development,2 Biochemistry and Molecular Biophysics,5 and Medicine,7 Columbia University College of Physicians and Surgeons, New York, New York 10032; Institute of Immunology and Molecular Genetics, Karlsruhe D-76133, Germany3; Institute of Molecular Biology and Genetics and Department of Molecular Biology, Seoul National University, Seoul 151-742, Korea4; and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 100216

Received 17 February 2000/Returned for modification 12 April 2000/Accepted 12 July 2000

We have previously described a SWI/SNF-related protein complex (PYR complex) that is restricted to definitive (adult-type) hematopoietic cells and that specifically binds DNA sequences containing long stretches of pyrimidines. Deletion of an intergenic DNA-binding site for this complex from a human beta -globin locus construct results in delayed human gamma - to beta -globin switching in transgenic mice, suggesting that the PYR complex acts to facilitate the switch. We now show that PYR complex DNA-binding activity also copurifies with subunits of a second type of chromatin-remodeling complex, nucleosome-remodeling deacetylase (NuRD), that has been shown to have both nucleosome-remodeling and histone deacetylase activities. Gel supershift assays using antibodies to the ATPase-helicase subunit of the NuRD complex, Mi-2 (CHD4), confirm that Mi-2 is a component of the PYR complex. In addition, we show that the hematopoietic cell-restricted zinc finger protein Ikaros copurifies with PYR complex DNA-binding activity and that antibodies to Ikaros also supershift the complex. We also show that NuRD and SWI/SNF components coimmunopurify with each other as well as with Ikaros. Competition gel shift experiments using partially purified PYR complex and recombinant Ikaros protein indicate that Ikaros functions as a DNA-binding subunit of the PYR complex. Our results suggest that Ikaros targets two types of chromatin-remodeling factors---activators (SWI/SNF) and repressors (NuRD)---in a single complex (PYR complex) to the beta -globin locus in adult erythroid cells. At the time of the switch from fetal to adult globin production, the PYR complex is assembled and may function to repress gamma -globin gene expression and facilitate gamma - to beta -globin switching.

* Corresponding author. Mailing address: Department of Genetics and Development, Hammer Health Sciences Room 1604, 701 West 168th Street, New York, NY 10032. Phone: (212) 305-4186. Fax: (212) 923-2090. E-mail: bank{at}cuccfa.ccc.columbia.edu.

Molecular and Cellular Biology, October 2000, p. 7572-7582, Vol. 20, No. 20
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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