Chromatin-associated HMG-17 is a major regulator of homeodomain transcription factor activity modulated by Wnt/beta-catenin signaling.
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/beta-catenin signaling pathway and adds to the diverse functions of beta-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. 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. 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/beta-catenin signaling in regulating HD transcriptional activity during development using HMG-17 as a molecular switch.
Amen
Melanie
M
Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA.
Espinoza
Herbert M
HM
Cox
Carol
C
Liang
Xiaowen
X
Wang
Jianbo
J
Link
Todd M E
TM
Brennan
Richard G
RG
Martin
James F
JF
Amendt
Brad A
BA
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D002843:Chromatin / Q000737:chemistry; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D024242:HMGN2 Protein / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D000097577:Homeobox Protein PITX2
D002843:Chromatin; D004247:DNA; D024242:HMGN2 Protein; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D000097577:Homeobox Protein PITX2