Transdifferentiation of fibroblasts into induced neuronal cells (iNs) by the neuron-specific transcription factors Brn2, Myt1l, and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress regarding the transcriptional hierarchy underlying transdifferentiation, the enablers of the concomitant epigenome resetting remain to be elucidated. Here, we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and combined inactivation. We found that Kmt2b, whose human homolog's mutations cause dystonia, is selectively required for iN conversion through suppression of the alternative myocyte program and induction of neuronal maturation genes. The identification of KMT2B-vulnerable targets allowed us, in turn, to expose, in a cohort of 225 patients, 45 unique variants in 39 KMT2B targets, which represent promising candidates to dissect the molecular bases of dystonia.

Department of Experimental Oncology IEO European Institute of Oncology IRCCS 20139 Milan Italy

Department of Experimental Oncology IEO European Institute of Oncology IRCCS 20139 Milan Italy; Department of Oncology and Hemato Oncology University of Milan 20122 Milan Italy

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General Faculty Hospital 12821 Prague Czech Republic

Department of Neurology Medical University Innsbruck 6020 Innsbruck Austria

Genomics Biotechnology Center Center for Molecular and Cellular Bioengineering Technische Universität Dresden 01069 Dresden Germany

Institut für Neurogenomik Helmholtz Zentrum München 85764 Munich Germany; Klinik und Poliklinik für Neurologie Klinikum rechts der Isar Technische Universität München 81675 Munich Germany

Institut für Neurogenomik Helmholtz Zentrum München 85764 Munich Germany; Lehrstuhl für Neurogenetik und Institut für Humangenetik Technische Universität München 81675 Munich Germany; Munich Cluster for Systems Neurology SyNergy 81829 Munich Germany

Klinik und Poliklinik für Neurologie Klinikum rechts der Isar Technische Universität München 81675 Munich Germany

San Raffaele Scientific Institute 20132 Milan Italy

San Raffaele Scientific Institute 20132 Milan Italy; National Research Council Institute of Neuroscience 20129 Milan Italy

Neurosci Insights. 2020 Jun 14;15:2633105520928068. doi: 10.1177/2633105520928068. PubMed

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