Computational Inference Tuned with Wet‐bench Results Yields a Model of the Transcriptional Regulatory Network Governing Zebrafish Periderm Differentiation

Early embryonic epidermis and oral epithelium in mammals stratify to generate outer protective layer, called the periderm, which prevents water loss and interepithelial adhesions among limbs and oral structures. Orofacial cleft is a structural birth defect which results from the mutations in transcription factors regulating oral periderm differentiation. In zebrafish, enveloping layer (EVL), also called periderm, is a simple squamous epithelial monolayer which arises from blastomeres. EVL differentiation shares many regulatory transcription factors (TFs) with mammalian periderm differentiation including Irf6 and Grhl3. Therefore, we use zebrafish EVL as a tractable model for the difficult‐to‐access mammalian oral periderm. We previously carried out ATAC‐seq in isolated periderm and flow‐through cells and found that the Grhl3, Klf17, Tfap2a, Cebpb, and Gata3 binding sites (TFBS) were enriched in periderm‐specific ATAC‐seq peaks, implicating these TFs in the transcriptional regulatory network (TRN) driving the periderm differentiation. In this study, we applied a computational method to infer the structure of the zebrafish periderm TRN, and, for use in tuning the parameters of the algorithm, we generated a reduced‐representation network model based on biologically‐validated edges.