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KMT2B Is Selectively Required for Neuronal Transdifferentiation, and Its Loss Exposes Dystonia Candidate Genes

2018; Cell Press; Volume: 25; Issue: 4 Linguagem: Inglês

10.1016/j.celrep.2018.09.067

2639-1856

Giulia Barbagiovanni, Pierre‐Luc Germain, Michael Zech, Sina Atashpaz, Pietro Lo Riso, Agnieszka D’Antonio‐Chronowska, Erika Tenderini, Massimiliano Caiazzo, Sylvia Boesch, Robert Jech, Bernhard Haslinger, Vania Broccoli, A. Francis Stewart, Juliane Winkelmann, Giuseppe Testa,

Genetics and Neurodevelopmental Disorders

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.