Abstract Body: Direct reprogramming has revolutionized the fields of stem cell biology and regenerative medicine. Targeted transdifferentiation of cells in situ holds significant promise in treating a large swathe of illness and injury including cardiovascular disease. However, much remains unknown about the molecular mechanisms of direct reprogramming, particularly its post-transcriptional regulation, including the role of m6a RNA modification. Here, by characterizing early changes in the m6a RNA methylome during reprogramming of fibroblasts toward three distinct lineages—cardiac, hepatic and neuronal—we identify lineage-specific features as well as common regulatory patterns. Our data reveal extensive changes in m6a methylome of direct reprogramming with clear impacts on cell fate decisions. Through loss-of-function screening of m6a readers, we uncovered Igf2bp1(insulin-like growth factor 2 mRNA binding protein 1) as a shared barrier to direct reprogramming. Further mechanistic studies will show how Igf2bp1 influences the reprogramming process mediated via m6a modifications. Collectively, our results present a fascinating portrait of m6a RNA methylome during direct reprogramming and reveal a key role of Igf2bp1 in maintaining cell fate, enhancing our mechanistic understanding of the reprogramming process.