Temporal changes in gene regulation during human tissue repair

The response to injury involves a complex series of events, including cellular migration and proliferation, inflammatory processes, and tissue remodeling. The oral mucosa exhibits a more regenerative repair response that resolves with minimal scarring when compared to skin. To investigate mechanisms driving this differential healing response, we integrated gene expression data from adult human palate and skin wounds over seven days with transcription factor binding data and protein-protein interaction data to estimate sample-specific gene regulatory networks. Comparative analysis between unwounded palate and skin networks revealed tissue-specific transcription factor targeting and gene set co-expression. Upon injury, global network changes between tissues were divergent, indicating distinct gene regulatory programs. Gene regulatory analyses revealed that the acute response to injury is characterized by transcription factor mediated gene repression, followed by tissue-specific gene activation at later healing stages. Notably, a subset of palate-specific transcription factors previously linked to regeneration in model organisms correlated with gene targeting and expression during acute injury. Specifically, BATF3 promoted cell migration and re-epithelialization after injury, but not proliferation. In summary, these findings highlight the temporal dynamics of transcription factors in wound response between palate and skin and provide insights into the gene regulatory mechanisms governing regenerative and non-regenerative healing.