Histone deacetylase 3 binds to and regulates the GCMa transcription factor.
Human GCMa transcription factor regulates expression of syncytin, a placental fusogenic protein mediating trophoblastic fusion. Recently, we have demonstrated that CBP-mediated GCMa acetylation underlies the activated cAMP/PKA signaling pathway that stimulates trophoblastic fusion. Because protein acetylation is a reversible modification governed by histone acetyltransferases (HATs) and histone deacetylase (HDACs), in this study we investigated the key HDACs responsible for deacetylation of GCMa and thus the reduction in GCMa activity to avoid unwanted fusion events that may have adverse effects on placental morphogenesis. We herein demonstrate that the HDAC inhibitor, trichostatin A (TSA), increases the level of acetylated GCMa and that HDAC1, 3, 4 and 5 interact with and deacetylate GCMa. Glutathione S-transferase (GST) pull-down assays further verified direct interaction between GCMa and HDAC3 or CBP and HDAC3. HDAC3 counteracts the transcriptional coactivator activity of CBP and the enhancement effect of CBP on GCMa-mediated transcriptional activation. Correlatively, we found in placental cells that HDAC3 associates with the proximal GCMa-binding site (pGBS) in the syncytin promoter and dissociates from pGBS in the presence of forskolin, which stimulates the association of CBP and GCMa with pGBS. Our studies support that trophoblastic fusion in placental morphogenesis depends on the regulation of GCMa activity by HAT and HDAC.
Chuang
Hsiao-Ching
HC
Graduate Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan.
Chang
Ching-Wen
CW
Chang
Geen-Dong
GD
Yao
Tso-Pang
TP
Chen
Hungwen
H
D001665:Binding Sites; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins; D010920:Placenta / Q000166:cytology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation; D000099186:Histone Deacetylase 3
D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D009479:Neuropeptides; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000099186:Histone Deacetylase 3; C491089:GCM1 protein, human; C012589:trichostatin A