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Molecular and Cellular Biology, June 2007, p. 4018-4027, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.01839-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Eos, MITF, and PU.1 Recruit Corepressors to Osteoclast-Specific Genes in Committed Myeloid Progenitors ^,

Rong Hu, Sudarshana M. Sharma, Agnieszka Bronisz, Ruchika Srinivasan, Uma Sankar, and Michael C. Ostrowski^*

Department of Molecular and Cellular Biochemistry and Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210

Received 28 September 2006/ Returned for modification 2 November 2006/ Accepted 7 March 2007

Transcription factors MITF and PU.1 collaborate to increase expression of target genes like cathepsin K (Ctsk) and acid phosphatase 5 (Acp5) during osteoclast differentiation. We show that these factors can also repress transcription of target genes in committed myeloid precursors capable of forming either macrophages or osteoclasts. The direct interaction of MITF and PU.1 with the zinc finger protein Eos, an Ikaros family member, was necessary for repression of Ctsk and Acp5. Eos formed a complex with MITF and PU.1 at target gene promoters and suppressed transcription through recruitment of corepressors CtBP (C-terminal binding protein) and Sin3A, but during osteoclast differentiation, Eos association with Ctsk and Acp5 promoters was significantly decreased. Subsequently, MITF and PU.1 recruited coactivators to these target genes, resulting in robust expression of target genes. Overexpression of Eos in bone marrow-derived precursors disrupted osteoclast differentiation and selectively repressed transcription of MITF/PU.1 targets, while small interfering RNA knockdown of Eos resulted in increased basal expression of Ctsk and Acp5. This work provides a mechanism to account for the modulation of MITF and PU.1 activity in committed myeloid progenitors prior to the initiation of osteoclast differentiation in response to the appropriate extracellular signals.

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* Corresponding author. Mailing address: 370A Tzagournis Medical Research Facility, Ohio State University, 420 West 12th Avenue, Columbus, OH 43210. Phone: (614) 688-3824. Fax: (614) 688-8727. E-mail: michael.ostrowski{at}osumc.edu

Published ahead of print on 2 April 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Rong Hu and Sudarshana M. Sharma were equal contributors to this work.

Present address: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710.

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Molecular and Cellular Biology, June 2007, p. 4018-4027, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.01839-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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