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.
- Klíčová slova
- KMT2B, MLL2, cell fate conversion, dystonia, epigenetics, histone H3 lysine 4 methylation, induced neuronal cells, mouse embryonic fibroblasts, myocytes, transdifferentiation,
- MeSH
- buněčná diferenciace genetika MeSH
- dystonie genetika MeSH
- embryo savčí cytologie MeSH
- epigeneze genetická MeSH
- fibroblasty cytologie MeSH
- genetické asociační studie * MeSH
- histonlysin-N-methyltransferasa metabolismus MeSH
- histony metabolismus MeSH
- lidé MeSH
- lysin metabolismus MeSH
- metylace MeSH
- myši knockoutované MeSH
- neurony metabolismus patologie MeSH
- protoonkogenní protein MLL metabolismus MeSH
- transdiferenciace buněk * genetika MeSH
- transkriptom genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- histonlysin-N-methyltransferasa MeSH
- histony MeSH
- Kmt2a protein, mouse MeSH Prohlížeč
- KMT2B protein, human MeSH Prohlížeč
- Kmt2d protein, mouse MeSH Prohlížeč
- lysin MeSH
- protoonkogenní protein MLL MeSH
