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Chromatin‐Associated HMG‐17 Is a Major Regulator of Transcription Factor Activity Modulated by Wnt/beta‐catenin Signaling
Author(s) -
Amendt Brad A,
Wang Jianbo
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.456.1
Subject(s) - chromatin , transcription factor , wnt signaling pathway , biology , microbiology and biotechnology , chromatin immunoprecipitation , chromatin remodeling , promoter , chemistry , gene expression , signal transduction , genetics , gene
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 a molecular switch regulating the transcriptional activity of several transcription factors. The switch utilizes the Wnt/beta‐catenin signaling pathway and adds to the diverse functions of beta‐catenin. A high affinity HMG‐17 interaction with the PITX2 homeodomain protein, LEF‐1 high mobility group protein, and FoxJ1 forkhead factor inhibits their DNA binding activity. The HMG‐17/PITX2 inactive complex is concentrated to specific nuclear regions primed for active transcription. Beta‐catenin forms a ternary complex with PITX2/HMG‐17 to switch it from a repressor to an activator complex. Without beta‐catenin, HMG‐17 can physically remove PITX2 from DNA to inhibit its transcriptional activity. shRNA to HMG‐17 decreases HMG‐17 expression and relieves the inhibitory action of HMG‐17. The PITX2/HMG‐17 regulatory complex acts independently of promoter targets and is a general mechanism for the control of transcriptional activity. Chromatin IP (ChIP) assays reveal acetylated Histone H4 and H3 interaction with the PITX2/HMG‐17 complex. HMG‐17 is developmentally regulated and its unique role during embryogenesis is revealed by the early embryonic lethality of HMG‐17 homozygous mice. This is a novel mechanism regulating transcriptional activity during development in which HMG‐17 recruits factors to chromatin and acts as a molecular switch. Support for this research was provided from grants DE13941 and DE18885 to BAA from the National Institute of Dental and Craniofacial Research.