Inhibition of p300 histone acetyltransferase activity in palate mesenchyme cells attenuates Wnt signaling via aberrant E-cadherin expression

Abstract

p300 is a multifunctional transcriptional coactivator that interacts with numerous transcription factors and exhibits protein/histone acetyltransferase activity. Loss of p300 function in humans and in mice leads to craniofacial defects. In this study, we demonstrated that inhibition of p300 histone acetyltransferase activity with the compound, C646, altered the expression of several genes, including Cdh1 (E-cadherin) in mouse maxillary mesenchyme cells, which are the cells that give rise to the secondary palate. The increased expression of plasma membrane-bound E-cadherin was associated with reduced cytosolic β-catenin, that led to attenuated signaling through the canonical Wnt pathway. Furthermore, C646 reduced both cell proliferation and the migratory ability of these cells. These results suggest that p300 histone acetyltransferase activity is critical for Wnt-dependent palate mesenchymal cell proliferation and migration, both processes that play a significant role in morphogenesis of the palate.

CBP/p300 inhibitor C646 prevents high glucose exposure induced neuroepithelial cell proliferation

“…*: p < .05 exposure in a dose-dependent manner (Grey column in Figure 6c). Consistently with our results showing inhibition of CBP and cellular proliferation via C646 (Warner, Smith, Smolenkova, Pisano, & Greene, 2016), addition of 5 μM C646 significantly stunted the proliferation rate at 4 hr after high glucose exposure (Figure 6c). Moreover, the Western blotting results (Figure 6d-e; Supporting Information Figure S1E) and H3S10-Pi immunofluorescent staining results (Figure 6f-g) indicated increased levels of H3S10pi induced by high glucose exposure and inhibition of C646.…”

PBX‐WNT‐P63‐IRF6pathway in nonsyndromic cleft lip and palate

“…Interestingly, missense variants in Klf4, an important regulator of periderm differentiation, have also been identified in NSCLP cases ( Liu et al, ). P300 is a multifunctional coactivator protein that exhibits protein/histone acetyltransferase activity and is essential for normal embryonic development and adult tissue homeostasis (Bhattacherjee et al, ; Warner, Smith, Smolenkova, Pisano, & Greene, ). Loss of p300 function in humans and in mice leads to craniofacial defects, possibly due to altered WNT and TGF‐β signaling (Warner et al, ).…”

Wnt signaling in orofacial clefts: crosstalk, pathogenesis and models

“…2). Furthermore, increased expression of Cdh1 in mouse maxillary mesenchymal cells during palatogenesis results in a reduction of cytosolic β-catenin (Warner et al, 2016) (Table 2). These studies suggest that Cdh1 may negatively regulate the canonical Wnt/β-catenin signaling pathway in humans and mice (Table 2, Fig.…”

“…The role of histone modifications in craniofacial development is less understood, but recent studies suggest that histone H3 acetylation can play a role in the formation of cleft palate in mouse due to dysregulation of Tgfβ signaling, although how this process affects Wnt signaling has not been demonstrated (Yuan et al, 2016). However, the histone acetyltransferase p300 (also known as Ep300) is important for gene regulation, and its ablation in mouse palatal mesenchyme cells results in altered Wnt signaling, as well as in aberrant Wnt-dependent proliferation and migration (Warner et al, 2016). An improved understanding of epigenetic regulation of Wnt signaling and related pathways may hold the key to addressing the impact of environmental and non-genetic factors on the presentation of orofacial clefts.…”