The transcription factor p63 is indispensable for epithelial stem cell proliferation/differentiation and epidermal development, with alterations in the p63 pathway underlying a subset of ectodermal dysplasias. Despite its critical role, the mechanisms regulating p63 expression remain poorly understood. Here, we identify an m6A‐mediated posttranscriptional mechanism controlling the expression of ΔNp63, the predominant functional p63 isoform in epidermal basal cells. We found that Cre‐mediated conditional deletion of Mettl16, encoding a conserved m6A methyltransferase, in mouse epithelial basal cells caused severe skin developmental abnormalities, reminiscent of human ectodermal dysplasias. RNA sequencing revealed significant downregulation of ΔNp63 and its target genes in Mettl16‐deficient skin, which linked METTL16 to p63 pathways. Mechanistically, we demonstrated that METTL16 directly binds to ΔNp63 mRNA to mediate its m6A modification; this modified ΔNp63 mRNA is subsequently recognized by the m6A reader IGF2BP2, which stabilizes ΔNp63 mRNA and thereby modulates its protein levels. Critically, restoration of ΔNp63 expression mitigated the epidermal defects in Mettl16‐deficient mice. Collectively, our findings uncover a novel METTL16‐m6A‐IGF2BP2‐ΔNp63 regulatory axis governing epidermal development, providing insights into the etiology of ectodermal dysplasias.
Hanjing Song, Jiani Zhang, Suman Huo et al.· The FASEB Journal· 0 citations
Tris (2-chloroethyl) phosphate (TCEP) is a widespread chlorinated organophosphate flame retardant, yet its biological impacts on saline aquatic biota remain largely undefined. Using the brine shrimp Artemia parthenogenetica, we examined TCEP toxicity across a concentration spectrum from environmentally relevant (2 µg/L) to acutely lethal levels (48-h LC₅₀ = 641.3 mg/L, 95% CI: 603.5-686.1 mg/L), revealing exceptional native tolerance. At 2 µg/L, no teratogenicity or oxidative damage occurred, though glutathione S-transferase (GST) detoxification genes GstS1 and GstO1 were transcriptionally induced, representing an early molecular perturbation. Across higher exposures (5-200 mg/L), TCEP dose-dependently impaired cyst hatching, provoked severe developmental malformations (up to 44%), and disrupted naupliar swimming. Biochemical assays showed catalase induction at 100-200 mg/L and lipid peroxidation with redox disturbance at 200 mg/L, abnormalities that extended into nauplii as widespread apoptosis. Transcriptomics at 200 mg/L identified 1464 differentially expressed genes enriched in cytochrome P450, RNA polymerase, and glutathione metabolism pathways. qPCR confirmed broad suppression of GST-associated genes (Gst5, Ugt2b14, Gpx3, GstO1) from 5 mg/L, whereas GstD7 exhibited a biphasic response and was ultimately downregulated at 200 mg/L. We propose that TCEP-driven suppression of glutathione-dependent detoxification undermines antioxidant capacity, and despite compensatory catalase upregulation, culminates in oxidative injury, apoptosis, and developmental defect. This work bridges environmental realism and mechanistic depth, providing a foundation for TCEP risk assessment in hypersaline ecosystems.
Hui-Lan Huang, Xian Xu, Lin Chen et al.· Ecotoxicology and Environmen...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
