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DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells

Author

Listed:
  • Andrea Lauria

    (Università di Torino
    Italian Institute for Genomic Medicine (IIGM))

  • Guohua Meng

    (Università di Torino
    Italian Institute for Genomic Medicine (IIGM))

  • Valentina Proserpio

    (Università di Torino
    Italian Institute for Genomic Medicine (IIGM))

  • Stefania Rapelli

    (Università di Torino)

  • Mara Maldotti

    (Università di Torino
    Italian Institute for Genomic Medicine (IIGM))

  • Isabelle Laurence Polignano

    (Università di Torino
    Italian Institute for Genomic Medicine (IIGM))

  • Francesca Anselmi

    (Università di Torino
    Italian Institute for Genomic Medicine (IIGM))

  • 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
    Italian Institute for Genomic Medicine (IIGM))

  • Francesco Neri

    (Università di Torino)

  • Salvatore Oliviero

    (Università di Torino
    Italian Institute for Genomic Medicine (IIGM))

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.

Suggested Citation

  • Andrea Lauria & Guohua Meng & Valentina Proserpio & Stefania Rapelli & Mara Maldotti & Isabelle Laurence Polignano & Francesca Anselmi & Danny Incarnato & Anna Krepelova & Daniela Donna & Chiara Levra, 2023. "DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35938-x
    DOI: 10.1038/s41467-023-35938-x
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    1. Bingnan Zhao & Xiuwei Yu & Jintong Shi & Shuangyu Ma & Shizhao Li & Haitao Shi & Shoubing Xia & Youqiong Ye & Yongchun Zhang & Yanhua Du & Qiong Wang, 2024. "A stepwise mode of TGFβ-SMAD signaling and DNA methylation regulates naïve-to-primed pluripotency and differentiation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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