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

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, Adrian Francis Stewart, Juliane Winkelmann, Giuseppe Testa

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)988-1001
Number of pages14
JournalCell Reports
Volume25
Issue number4
DOIs
Publication statusPublished - Oct 23 2018

Fingerprint

Dystonia
Fibroblasts
Genes
Histones
Lysine
Neurons
Transcription Factors
Epigenomics
Muscle Cells
Mutation

Keywords

  • cell fate conversion
  • dystonia
  • epigenetics
  • histone H3 lysine 4 methylation
  • induced neuronal cells
  • KMT2B
  • MLL2
  • mouse embryonic fibroblasts
  • myocytes
  • transdifferentiation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

KMT2B Is Selectively Required for Neuronal Transdifferentiation, and Its Loss Exposes Dystonia Candidate Genes. / Barbagiovanni, Giulia; Germain, Pierre Luc; Zech, Michael; Atashpaz, Sina; Lo Riso, Pietro; D'Antonio-Chronowska, Agnieszka; Tenderini, Erika; Caiazzo, Massimiliano; Boesch, Sylvia; Jech, Robert; Haslinger, Bernhard; Broccoli, Vania; Stewart, Adrian Francis; Winkelmann, Juliane; Testa, Giuseppe.

In: Cell Reports, Vol. 25, No. 4, 23.10.2018, p. 988-1001.

Research output: Contribution to journalArticle

Barbagiovanni, G, Germain, PL, Zech, M, Atashpaz, S, Lo Riso, P, D'Antonio-Chronowska, A, Tenderini, E, Caiazzo, M, Boesch, S, Jech, R, Haslinger, B, Broccoli, V, Stewart, AF, Winkelmann, J & Testa, G 2018, 'KMT2B Is Selectively Required for Neuronal Transdifferentiation, and Its Loss Exposes Dystonia Candidate Genes', Cell Reports, vol. 25, no. 4, pp. 988-1001. https://doi.org/10.1016/j.celrep.2018.09.067
Barbagiovanni, Giulia ; Germain, Pierre Luc ; Zech, Michael ; Atashpaz, Sina ; Lo Riso, Pietro ; D'Antonio-Chronowska, Agnieszka ; Tenderini, Erika ; Caiazzo, Massimiliano ; Boesch, Sylvia ; Jech, Robert ; Haslinger, Bernhard ; Broccoli, Vania ; Stewart, Adrian Francis ; Winkelmann, Juliane ; Testa, Giuseppe. / KMT2B Is Selectively Required for Neuronal Transdifferentiation, and Its Loss Exposes Dystonia Candidate Genes. In: Cell Reports. 2018 ; Vol. 25, No. 4. pp. 988-1001.
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AU - Barbagiovanni, Giulia

AU - Germain, Pierre Luc

AU - Zech, Michael

AU - Atashpaz, Sina

AU - Lo Riso, Pietro

AU - D'Antonio-Chronowska, Agnieszka

AU - Tenderini, Erika

AU - Caiazzo, Massimiliano

AU - Boesch, Sylvia

AU - Jech, Robert

AU - Haslinger, Bernhard

AU - Broccoli, Vania

AU - Stewart, Adrian Francis

AU - Winkelmann, Juliane

AU - Testa, Giuseppe

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N2 - 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.

AB - 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.

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