Nucleic Acids Research Advance Access originally published online on November 27, 2007
Nucleic Acids Research 2008 36(2):462-476; doi:10.1093/nar/gkm1047
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Nucleic Acids Research, 2008, Vol. 36, No. 2 462-476
© 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
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. Revised November 1, 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.