BioProject

Direct reprogramming from fibroblasts to neurons induces widespread cellular and transcriptional reconfigurations. More...

Direct reprogramming from fibroblasts to neurons induces widespread cellular and transcriptional reconfigurations. In this study, we characterized global epigenomic changes during direct reprogramming using whole-genome base-resolution DNA methylome (mC) sequencing. We found that the pioneer transcription factor Ascl1 alone is sufficient for inducing robust non-CG methylation (mCH) accumulation in reprogrammed cells, but co-expression of Brn2 and Mytl1 was required to establish a global mCH pattern reminiscent of mature cortical neurons. Ascl1 alone induced strong promoter CG methylation (mCG) of fibroblast specific genes, while BAM overexpression additionally targets a competing myogenic program and directs a more faithful conversion to neuronal cells. Ascl1 induces local demethylation at its binding sites. Surprisingly, co-expression with Brn2 and Mytl1 inhibited the ability of Ascl1 to induce demethylation, suggesting a contextual regulation of transcription factor - epigenome interaction. Finally, we found that de novo methylation by DNMT3A is required for efficient neuronal reprogramming. Overall design: MethylC-seq of direct reprogramming from fibroblast to neuron Less...