DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility

Francesco Ferrari, Laura Arrigoni, Henriette Franz, Annalisa Izzo, Ludmila Butenko, Eirini Trompouki, Tanja Vogel () and Thomas Manke ()
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Francesco Ferrari: Max Planck Institute of Immunobiology and Epigenetics
Laura Arrigoni: Max Planck Institute of Immunobiology and Epigenetics
Henriette Franz: Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg
Annalisa Izzo: Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg
Ludmila Butenko: Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg
Eirini Trompouki: Max Planck Institute of Immunobiology and Epigenetics
Tanja Vogel: Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg
Thomas Manke: Max Planck Institute of Immunobiology and Epigenetics

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract During neuronal differentiation, the transcriptional profile and the epigenetic context of neural committed cells is subject to significant rearrangements, but a systematic quantification of global histone modification changes is still missing. Here, we show that H3K79me2 increases and H3K27ac decreases globally during in-vitro neuronal differentiation of murine embryonic stem cells. DOT1L mediates all three degrees of methylation of H3K79 and its enzymatic activity is critical to modulate cellular differentiation and reprogramming. In this context, we find that inhibition of DOT1L in neural progenitor cells biases the transcriptional state towards neuronal differentiation, resulting in transcriptional upregulation of genes marked with H3K27me3 on the promoter region. We further show that DOT1L inhibition affects accessibility of SOX2-bound enhancers and impairs SOX2 binding in neural progenitors. Our work provides evidence that DOT1L activity gates differentiation of progenitors by allowing SOX2-dependent transcription of stemness programs.

Date: 2020
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DOI: 10.1038/s41467-020-19001-7

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