Direct reprogramming of mesoderm-derived fibroblasts into induced neurons (iNs) by neuronal-specific transcription factors Brn2, Myt1l and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress on the transcriptional hierarchy underlying transdifferentiation, the concomitant epigenome resetting and its drivers remain elusive. Here we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and compound inactivation. We find that Kmt2b, whose mutations cause human brain disorder dystonia, is selectively required for iN conversion through the suppression of the alternative myocyte program and the induction of neuronal maturation genes. The identification of KMT2B vulnerable targets that are specific to cell fate reassignment allowed in turn the identification of new dystonia-relevant variants and genes in a large cohort of patients, discovering 45 unique protein-impactful alterations in 39 KMT2B-targets that constitute promising candidates for KMT2B-related dystonia causation.
