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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)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift Cell Reports
Quellenangaben Band: 25, Heft: 4, Seiten: 988-1001 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)