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

KMT2B is selectively required for neuronal transdifferentiation and its loss exposes dystonia candidate genes.

Cell Rep. 25, 988-1001 (2018)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Kmt2b ; Mll2 ; Cell Fate Conversion ; Dystonia ; Epigenetics ; Histone H3 Lysine 4 Methylation ; Induced Neuronal Cells ; Mouse Embryonic Fibroblasts ; Myocytes ; Transdifferentiation; Histone-methyltransferase Mll2; Embryonic Stem-cells; Differentiation; Fibroblasts; Haploinsufficiency; Mutations; Reveal; Mouse

ISSN (print) / ISBN 2211-1247

e-ISSN 2211-1247

Journal Cell Reports

Quellenangaben Volume: 25, Issue: 4, Pages: 988-1001

Publisher Cell Press

Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)