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Nucleic Acids Research Advance Access published online on November 27, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm1047
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Chromatin-associated HMG-17 is a major regulator of homeodomain transcription factor activity modulated by Wnt/β-catenin signaling

Melanie Amen1, Herbert M. Espinoza1, Carol Cox2, Xiaowen Liang1, Jianbo Wang1, Todd M. E. Link3, Richard G. Brennan3, James F. Martin1 and Brad A. Amendt1,*

1Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, 2Oklahoma University Health Science Center, Oklahoma City, OK and 3Department of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

*To whom correspondence should be addressed. Tel: +1 713 677 7402; Fax: +1 713 677 7784; Email: bamendt{at}ibt.tamhsc.edu

Received August 31, 2007. Accepted November 1, 2007.

Homeodomain (HD) transcriptional activities are tightly regulated during embryogenesis and require protein interactions for their spatial and temporal activation. The chromatin-associated high mobility group protein (HMG-17) is associated with transcriptionally active chromatin, however its role in regulating gene expression is unclear. This report reveals a unique strategy in which, HMG-17 acts as a molecular switch regulating HD transcriptional activity. The switch utilizes the Wnt/β-catenin signaling pathway and adds to the diverse functions of β-catenin. A high-affinity HMG-17 interaction with the PITX2 HD protein inhibits PITX2 DNA-binding activity. The HMG-17/PITX2 inactive complex is concentrated to specific nuclear regions primed for active transcription. β-Catenin forms a ternary complex with PITX2/HMG-17 to switch it from a repressor to an activator complex. Without β-catenin, HMG-17 can physically remove PITX2 from DNA to inhibit its transcriptional activity. The PITX2/HMG-17 regulatory complex acts independently of promoter targets and is a general mechanism for the control of HD transcriptional activity. HMG-17 is developmentally regulated and its unique role during embryogenesis is revealed by the early embryonic lethality of HMG-17 homozygous mice. This mechanism provides a new role for canonical Wnt/β-catenin signaling in regulating HD transcriptional activity during development using HMG-17 as a molecular switch.


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