The SynMuvA lin-15A licenses natural transdifferentiation by antagonizing identity safeguarding mechanisms

The mechanisms that restrict or enable latent cellular plasticity have attracted growing interest over the past decade, with important implications for cancer and regenerative therapies. However, the diversity of both pro- and anti-plasticity mechanisms remains incompletely understood. Here, we identify the THAP domain gene lin-15A as a novel factor involved in the natural rectal-to-neuronal Y-to-PDA transdifferentiation in Caenorhabditis elegans. Our genetic analyses show that lin-15A acts in parallel to previously described plasticity factors. Null mutant suggests that, rather than driving the process, LIN-15A licenses its initiation by antagonizing several chromatin-modifying complexes known to safeguard differentiated cell identities. In addition, our data show that even cells developmentally programmed to undergo transdifferentiation exhibit reprogramming barriers. Interestingly, lin-15A is not a core plasticity factor per se but acts as one specifically in the Y cell context. Together, our findings support a model in which diverse molecular activities coordinate controlled cell identity conversions: plasticity factors function as Drivers, while others like lin-15A, termed here transdifferentiation Licensers, attenuate identity safeguarding mechanisms, thereby facilitating transdifferentiation.