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

G. Barbagiovanni, PL. Germain, M. Zech, S. Atashpaz, P. Lo Riso, A. D'Antonio-Chronowska, E. Tenderini, M. Caiazzo, S. Boesch, R. Jech, B. Haslinger, V. Broccoli, AF. Stewart, J. Winkelmann, G. Testa,

. 2018 ; 25 (4) : 988-1001. [pub] 20181023

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc19045175

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.

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$a Transdifferentiation of fibroblasts into induced neuronal cells (iNs) by the neuron-specific transcription factors Brn2, Myt1l, and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress regarding the transcriptional hierarchy underlying transdifferentiation, the enablers of the concomitant epigenome resetting remain to be elucidated. Here, we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and combined inactivation. We found that Kmt2b, whose human homolog's mutations cause dystonia, is selectively required for iN conversion through suppression of the alternative myocyte program and induction of neuronal maturation genes. The identification of KMT2B-vulnerable targets allowed us, in turn, to expose, in a cohort of 225 patients, 45 unique variants in 39 KMT2B targets, which represent promising candidates to dissect the molecular bases of dystonia.
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$a Atashpaz, Sina $u Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy.
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$a Lo Riso, Pietro $u Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy.
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$a Tenderini, Erika $u Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139 Milan, Italy.
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$a Caiazzo, Massimiliano $u San Raffaele Scientific Institute, 20132 Milan, Italy.
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$a Boesch, Sylvia $u Department of Neurology, Medical University Innsbruck, 6020 Innsbruck, Austria.
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$a Jech, Robert $u Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General Faculty Hospital, 12821 Prague, Czech Republic.
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$a Haslinger, Bernhard $u Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
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$a Broccoli, Vania $u San Raffaele Scientific Institute, 20132 Milan, Italy; National Research Council (CNR), Institute of Neuroscience, 20129 Milan, Italy.
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$a Stewart, Adrian Francis $u Genomics, Biotechnology Center, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, 01069 Dresden, Germany.
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$a Winkelmann, Juliane $u Institut für Neurogenomik, Helmholtz Zentrum München, 85764 Munich, Germany; Lehrstuhl für Neurogenetik und Institut für Humangenetik, Technische Universität München, 81675 Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, 81829 Munich, Germany.
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$a Testa, Giuseppe $u 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. Electronic address: giuseppe.testa@ieo.it.
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