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. Barbagiovanni et al. demonstrate that KMT2B, in contrast to KMT2A, is fundamental for the epigenetic and transcriptomic resetting underlying transdifferentiation of fibroblasts into induced neuronal cells (iNs), acting both in the suppression of alternative fates and in the promotion of iN maturation. Transdifferentiation-specific KMT2B targets reveal dystonia-causative gene candidates.

KMT2B Is Selectively Required for Neuronal Transdifferentiation, and Its Loss Exposes Dystonia Candidate Genes / G. Barbagiovanni, P. Germain, M. Zech, S. Atashpaz, P. Lo Riso, A. D'Antonio-Chronowska, E. Tenderini, M. Caiazzo, S. Boesch, R. Jech, B. Haslinger, V. Broccoli, A.F. Stewart, J. Winkelmann, G. Testa. - In: CELL REPORTS. - ISSN 2211-1247. - 25:4(2018 Oct 23), pp. 988-1001.

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

G. Barbagiovanni;P. Germain;P. Lo Riso;G. Testa
Ultimo
2018

Abstract

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. Barbagiovanni et al. demonstrate that KMT2B, in contrast to KMT2A, is fundamental for the epigenetic and transcriptomic resetting underlying transdifferentiation of fibroblasts into induced neuronal cells (iNs), acting both in the suppression of alternative fates and in the promotion of iN maturation. Transdifferentiation-specific KMT2B targets reveal dystonia-causative gene candidates.
cell fate conversion; dystonia; epigenetics; histone H3 lysine 4 methylation; induced neuronal cells; KMT2B; MLL2; mouse embryonic fibroblasts; myocytes; transdifferentiation; Biochemistry, Genetics and Molecular Biology (all)
Settore BIO/11 - Biologia Molecolare
Settore BIO/10 - Biochimica
Settore BIO/13 - Biologia Applicata
Settore BIO/12 - Biochimica Clinica e Biologia Molecolare Clinica
Settore BIO/18 - Genetica
Settore MED/03 - Genetica Medica
Settore MED/04 - Patologia Generale
   Modeling Disease through Cell Reprogramming: a Translational Approach to the Pathogenesis of Syndromes Caused by Symmetrical Gene Dosage Imbalances
   DISEASEAVATARS
   EUROPEAN COMMISSION
   FP7
   616441

   Progetto Bandiera Epigenomica - EMENDAMENTO I
   EPIGEN
   MINISTERO DELL'ISTRUZIONE E DEL MERITO
23-ott-2018
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/598388
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