Meg3-NONO-RAR axis mediates RA pathway activation in TCDD-induced cleft palate

Dioxins, a group of environmental pollutants, can cause developmental toxicity through interaction with the aromatic hydrocarbon receptor (AHR). Retinoic acid (RA) functions via binding to retinoic acid receptor (RAR)/retinoid X receptor (RXR). Both AHR and RA pathways can be activated by dioxins. TCDD or atRA exposure similarly alters the expression of the long non-coding RNA (lncRNA) Meg3 in mouse palatal tissue. This study further examined the mechanism of TCDD-induced cleft palate (CP) via the RA pathway in mouse embryonic palatal mesenchymal (MEPM) cells. Results showed that in MEPM cells TCDD treatment increased Meg3 and RARA expression, inhibited cell proliferation, and had a synergistic effect with atRA. RNA pull-down-MS and RIP assays revealed that Meg3 binds to NONO, which belongs to the drosophila behavior human splicing family (DBHS) and have been reported to be associated with cell cycle regulation. NONO interacts with RAR and inhibits RARA expression. TCDD and atRA treatment reduced NONO expression. Silencing Meg3 raised NONO levels and mitigated the impact of TCDD or atRA on RA pathway activation, cell proliferation and survival. These findings suggest that TCDD affects Meg3 and NONO expression and the RA pathway activation, Meg3 interacts with NONO which may regulate RARA in palatal tissue. Thus, we propose that the RA pathway activation in TCDD-induced cleft palate may be mediated by the Meg3-NONO-RAR axis.