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Enhancer-associated H3K4 methylation safeguards in vitro germline competence

Author

Listed:
  • Tore Bleckwehl

    (University of Cologne)

  • Giuliano Crispatzu

    (University of Cologne
    University Hospital Cologne
    University of Cologne)

  • Kaitlin Schaaf

    (University of Cologne)

  • Patricia Respuela

    (University of Cologne
    CSIC/University of Cantabria)

  • Michaela Bartusel

    (University of Cologne
    Massachusetts Institute of Technology)

  • Laura Benson

    (Babraham Institute)

  • Stephen J. Clark

    (Babraham Institute)

  • Kristel M. Dorighi

    (Stanford University School of Medicine)

  • Antonio Barral

    (Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • Magdalena Laugsch

    (University of Cologne
    Heidelberg University Hospital)

  • Wilfred F. J. van IJcken

    (Erasmus University Medical Center Rotterdam, Center for Biomics)

  • Miguel Manzanares

    (Centro Nacional de Investigaciones Cardiovasculares (CNIC)
    Centro de Biología Molecular Severo Ochoa (CBMSO), CSIC-UAM)

  • Joanna Wysocka

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Wolf Reik

    (Babraham Institute
    University of Cambridge
    Wellcome Trust Sanger Institute)

  • Álvaro Rada-Iglesias

    (University of Cologne
    University of Cologne
    CSIC/University of Cantabria)

Abstract

Germline specification in mammals occurs through an inductive process whereby competent cells in the post-implantation epiblast differentiate into primordial germ cells (PGC). The intrinsic factors that endow epiblast cells with the competence to respond to germline inductive signals remain unknown. Single-cell RNA sequencing across multiple stages of an in vitro PGC-like cells (PGCLC) differentiation system shows that PGCLC genes initially expressed in the naïve pluripotent stage become homogeneously dismantled in germline competent epiblast like-cells (EpiLC). In contrast, the decommissioning of enhancers associated with these germline genes is incomplete. Namely, a subset of these enhancers partly retain H3K4me1, accumulate less heterochromatic marks and remain accessible and responsive to transcriptional activators. Subsequently, as in vitro germline competence is lost, these enhancers get further decommissioned and lose their responsiveness to transcriptional activators. Importantly, using H3K4me1-deficient cells, we show that the loss of this histone modification reduces the germline competence of EpiLC and decreases PGCLC differentiation efficiency. Our work suggests that, although H3K4me1 might not be essential for enhancer function, it can facilitate the (re)activation of enhancers and the establishment of gene expression programs during specific developmental transitions.

Suggested Citation

  • Tore Bleckwehl & Giuliano Crispatzu & Kaitlin Schaaf & Patricia Respuela & Michaela Bartusel & Laura Benson & Stephen J. Clark & Kristel M. Dorighi & Antonio Barral & Magdalena Laugsch & Wilfred F. J., 2021. "Enhancer-associated H3K4 methylation safeguards in vitro germline competence," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26065-6
    DOI: 10.1038/s41467-021-26065-6
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    Cited by:

    1. Abrar Aljahani & Peng Hua & Magdalena A. Karpinska & Kimberly Quililan & James O. J. Davies & A. Marieke Oudelaar, 2022. "Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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