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

Author:

O'Neill David W.1,Schoetz Stuti S.2,Lopez Rocio A.2,Castle Madalyn2,Rabinowitz Lisa2,Shor Erika2,Krawchuk Dayana2,Goll Mary G.2,Renz Manfred3,Seelig Hans-Peter3,Han Sunmi4,Seong Rho H.4,Park Sang D.4,Agalioti Theodora5,Munshi Nikhil5,Thanos Dimitrios5,Erdjument-Bromage Hediye6,Tempst Paul6,Bank Arthur27

Affiliation:

1. Departments of Pathology,1

2. Genetics and Development,2

3. Institute of Immunology and Molecular Genetics, Karlsruhe D-76133, Germany 3 ;

4. Institute of Molecular Biology and Genetics and Department of Molecular Biology, Seoul National University, Seoul 151-742, Korea 4 ; and

5. Biochemistry and Molecular Biophysics, 5 and

6. Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 100216

7. Medicine, 7 Columbia University College of Physicians and Surgeons, New York, New York 10032;

Abstract

ABSTRACT 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 β-globin locus construct results in delayed human γ- to β-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 β-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 γ-globin gene expression and facilitate γ- to β-globin switching.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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