DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells

Andrea Lauria, Guohua Meng, Valentina Proserpio, Stefania Rapelli, Mara Maldotti, Isabelle Laurence Polignano, Francesca Anselmi, Danny Incarnato, Anna Krepelova, Daniela Donna, Chiara Levra Levron, Giacomo Donati, Ivan Molineris, Francesco Neri and Salvatore Oliviero ()
Additional contact information
Andrea Lauria: Università di Torino
Guohua Meng: Università di Torino
Valentina Proserpio: Università di Torino
Stefania Rapelli: Università di Torino
Mara Maldotti: Università di Torino
Isabelle Laurence Polignano: Università di Torino
Francesca Anselmi: Università di Torino
Danny Incarnato: University of Groningen
Anna Krepelova: Università di Torino
Daniela Donna: Università di Torino
Chiara Levra Levron: Università di Torino
Giacomo Donati: Università di Torino
Ivan Molineris: Università di Torino
Francesco Neri: Università di Torino
Salvatore Oliviero: Università di Torino

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract The correct establishment of DNA methylation patterns during mouse early development is essential for cell fate specification. However, the molecular targets as well as the mechanisms that determine the specificity of the de novo methylation machinery during differentiation are not completely elucidated. Here we show that the DNMT3B-dependent DNA methylation of key developmental regulatory regions at epiblast-like cells (EpiLCs) provides an epigenetic priming that ensures flawless commitment at later stages. Using in vitro stem cell differentiation and loss of function experiments combined with high-throughput genome-wide bisulfite-, bulk-, and single cell RNA-sequencing we dissected the specific role of DNMT3B in cell fate. We identify DNMT3B-dependent regulatory elements on the genome which, in Dnmt3b knockout (3BKO), impair the differentiation into meso-endodermal (ME) progenitors and redirect EpiLCs towards the neuro-ectodermal lineages. Moreover, ectopic expression of DNMT3B in 3BKO re-establishes the DNA methylation of the master regulator Sox2 super-enhancer, downmodulates its expression, and restores the expression of ME markers. Taken together, our data reveal that DNMT3B-dependent methylation at the epiblast stage is essential for the priming of the meso-endodermal lineages and provide functional characterization of the de novo DNMTs during EpiLCs lineage determination.

Date: 2023
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DOI: 10.1038/s41467-023-35938-x

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