Histone deacetylase 3 binds to and regulates the GCMa transcription factor

Abstract

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.

Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast

“…At the transcriptional level, GCM1 was shown to be regulated by a functional cAMP-responsive element and a histone deacetylase 3-binding motif in the promoter region upstream of the start codon. 21,23,24 GCM1 was shown to regulate the expression of different proteins, such as the placental growth factor, 25 a human aromatase, 26 and the fusion protein, Syncytin1. 13 A GCM1-binding motif was also found in the promotor of the human chorionic gonadotropin a-subunit.…”

HDAC3: taking the SMRT-N-CoRrect road to repression

“…In addition, HDAC3-mediated deacetylation of p53 upon shear stress appears to be critical for differentiation of stem cells into epithelial cells (Zeng et al, 2006). Furthermore, HDAC3 deacetylates myocyte enhancer factor 2, a transcription factor important for differentiation, apoptosis and survival of different cell types (Gregoire et al, 2007), as well as glial cell missing (GCMa), which is important in development and differentiation (Chuang et al, 2006). Interestingly, in both cases, HDAC3 was also found to deacetylate the responsible acetyltransferases (PCAF and p300/CBP) for these proteins (Chuang et al, 2006;Gregoire et al, 2007).…”

“…Furthermore, HDAC3 deacetylates myocyte enhancer factor 2, a transcription factor important for differentiation, apoptosis and survival of different cell types (Gregoire et al, 2007), as well as glial cell missing (GCMa), which is important in development and differentiation (Chuang et al, 2006). Interestingly, in both cases, HDAC3 was also found to deacetylate the responsible acetyltransferases (PCAF and p300/CBP) for these proteins (Chuang et al, 2006;Gregoire et al, 2007). Moreover, a subset of N-CoR-HDAC3 complex copurifies with CBP in HeLa cells and N-CoR can interact directly with CBP (Cowger and Torchia, 2006).…”

PMA-induced GCMa phosphorylation stimulates its transcriptional activity and degradation

“…Recent studies have shown that the expression level and transcriptional activity of GCMa are regulated by its post-translational modifications. The acetylation and deacetylation by CRE-binding protein-binding protein (CBP) and histone deacetylase 3 (HDAC3) regulate the protein stability of GCMa (7,13), and the sumoylation destabilizes the interaction between GCMa and the specific DNA sequence called GCM motif (6,12). The phosphorylation of GCMa on serine 322 results in its ubiquitination and degradation (11).…”