OR14

Direct neuronal reprogramming is a promising cell therapy approach to regenerate neurons from local glial cells. However, mechanisms of epigenome remodelling and co-factors facilitating this process are largely unknown. We combined single-cell multiomics with genome-wide profiling of 3D nuclear architecture and DNA methylation in astrocyte-to-neuron reprogramming mediated by Neurogenin2 and its more potent phosphorylation-deficient form, respectively. This revealed Ngn2-driven multi-layered chromatin remodelling at dynamic enhancer-gene interactions sites with stronger effects achieved by the phosphorylation-deficient form. However, additional DNA-binding of the phosphorylation-deficient form could not explain its higher reprogramming capacity. Instead, we identified a novel co-factor, Yy1, recruited by direct interaction with Ngn2 to its neurogenic sites. Upon deletion of Yy1, Ngn2 binding is largely unaltered, but activation of key neuronal enhancers and genes is impaired and reprogramming is severely impaired. Thus, our work highlights the key role of interactors of proneural factors in direct neuronal reprogramming and will facilitate the improvement of this promising cell therapy approach to repair the injured brain.