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Nucleic Acids Research Advance Access published online on December 26, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm1131
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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

Proteomic screen defines the hepatocyte nuclear factor 1{alpha}-binding partners and identifies HMGB1 as a new cofactor of HNF1{alpha}

Miao Yu1,2,3, Jian Wang1,2,3, Wei Li1,2,3, Yan Zhi Yuan1,2,3, Chang Yan Li1,3, Xiao Hong Qian1,2,3, Wang Xiang Xu1,3, Yi Qun Zhan1,3 and Xiao Ming Yang1,2,3,*

1Beijing Institute of Radiation Medicine, Beijing, 100850, 2Beijing Proteomics Research Center, Beijing, 102206 and 3State Key Laboratory of Proteomics, Beijing, 100850, P. R. China

*To whom correspondence should be addressed. Tel: +86 10 66931424; Fax: +86 10 68212874; Email: xmyang2{at}nic.bmi.ac.cn or xiaomingyang{at}sina.com

Received September 11, 2007. Revised November 28, 2007. Accepted December 5, 2007.

Hepatocyte nuclear factor (HNF)-1{alpha} is one of the liver-enriched transcription factors involved in many tissue-specific expressions of hepatic genes. The molecular mechanisms for determining HNF1{alpha}-mediated transactivation have not been explained fully. To identify unknown proteins that interact with HNF1{alpha}, we developed a co-IP-MS strategy to search HNF1{alpha} interactions, and high mobility group protein-B1 (HMGB1), a chromosomal protein, was identified as a novel HNF1{alpha}-interacting protein. In vitro glutathione S-transferase pull-down and in vivo co-immunoprecipitation studies confirmed an interaction between HMGB1 and HNF1{alpha}. The protein–protein interaction was mediated through the HMG box domains of HMGB1 and the homeodomain of HNF1{alpha}. Furthermore, electrophoretic mobility shift assay and chromatin-immunoprecipitation assay demonstrated that HMGB1 was recruited to endogenous HNF1{alpha}-responsive promoters and enhanced HNF1{alpha} binding to its cognate DNA sequences. Moreover, luciferase reporter analyses showed that HMGB1 potentiated the transcriptional activities of HNF1{alpha} in cultured cells, and downregulation of HMGB1 by RNA interference specifically affected the HNF1{alpha}-dependent gene expression in HepG2 cell. Taken together, these findings raise the intriguing possibility that HMGB1 is a new cofactor of HNF1{alpha} and participates in HNF1{alpha}-mediated transcription regulation through protein–protein interaction.


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