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J. Biol. Chem., Vol. 278, Issue 48, 47792-47802, November 28, 2003

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HoxA10 Represses Gene Transcription in Undifferentiated Myeloid Cells by Interaction with Histone Deacetylase 2^*

YuFeng Lu¶, Inna Goldenberg¶, Ling Bei¶, Jelena Andrejic||, and Elizabeth A. Eklund**

From the Fineberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, ^¶Chicago Lakeside Veterans Affairs Hospital, Chicago, Illinois 60611, and the ^||Birmingham Veterans Affairs Hospital, Birmingham, Alabama 35294

The homeodomain proteins, HoxA10 and Pbx1a, interact with negative cis elements to repress gene transcription in undifferentiated myeloid cells. The CYBB and NCF2 genes, which encode the gp91^PHOX and p67^PHOX proteins, are two such HoxA10-Pbx1a target genes. In previous studies, we found that HoxA10-Pbx1a represses transcription of these genes by two mechanisms: competition for DNA binding with transcriptional activators and endogenous repression activity. In these studies, we identify a novel molecular mechanism of endogenous transcriptional repression by HoxA10-Pbx1a. Endogenous repression activity of other Hox-Pbx1a complexes requires recruitment of transcriptional co-repressor proteins by Pbx1a. In contrast, our investigations have determined that HoxA10 has Pbx1a-independent endogenous repression activity. We find that this transcriptional repression activity is abrogated by histone deacetylase inhibitors, suggesting involvement of co-repressor proteins. Consistent with this, we identify HoxA10 amino acids 224–249 as a Pbx1-independent repression domain, which interacts with histone deacetylase 2. We have determined that this HoxA10 domain is not conserved with other Abd Hox proteins, although homology exists with other transcription factors and co-repressors. Understanding the roles different Hox proteins play in myeloid differentiation is a challenging problem. Our results suggest that insight into this problem can be obtained from biochemical characterization of the various molecular mechanisms of Hox protein function.

Received for publication, June 4, 2003 , and in revised form, September 22, 2003.

^* This work was supported by a Veterans Affairs Merit Review, a Leukemia and Lymphoma Society of America Translational Research Award, and National Institutes of Health Grant CA95266 (to E. A. E.). 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.

^** To whom correspondence should be addressed: Dept. of Medicine (Hematology/Oncology), Rm. 8527, Northwestern University Medical School, 710 N. Fairbanks Ct., Olson Pavilion, Chicago, IL 60611. E-mail: e-eklund{at}northwestern.edu.

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