Epigenetic priming of embryonic enhancer elements coordinates developmental gene networks

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Embryonic development requires the accurate spatiotemporal execution of cell lineage-specific gene expression programs, which are controlled by transcriptional enhancers. Developmental enhancers adopt a primed chromatin state prior to their activation; however how this primed enhancer state is established, maintained, and how it affects the regulation of developmental gene networks remains poorly understood. Here, we use comparative multi-omic analyses of human and mouse early embryonic development to identify subsets of post-gastrulation lineage-specific enhancers which are epigenetically primed ahead of their activation, marked by the histone modification H3K4me1 within the epiblast. We show that epigenetic priming occurs at lineage-specific enhancers for all three germ layers, and that epigenetic priming of enhancers confers lineage-specific regulation of key developmental gene networks. Surprisingly in some cases, lineage-specific enhancers are epigenetically marked already in the zygote, weeks before their activation during lineage specification. Moreover, we outline a generalisable strategy to use naturally occurring human genetic variation to delineate important sequence determinants of primed enhancer function. Our findings identify an evolutionarily conserved program of enhancer priming and begin to dissect the temporal dynamics and mechanisms of its establishment and maintenance during early mammalian development.

Authors 15

1. Christopher D Todd corresponding

   Babraham Institute · University of Cambridge

   Affiliation as printed

   Altos Labs Cambridge Institute of Science, Granta Park, Cambridge, UK

   Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK

2. Jannat Ijaz

   Babraham Institute · University of Cambridge

   Affiliation as printed

   Altos Labs Cambridge Institute of Science, Granta Park, Cambridge, UK

   Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK

3. Fereshteh Torabi

   Babraham Institute · Wellcome Sanger Institute

   Affiliation as printed

   Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK

   Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK

4. Oleksandr Dovgusha

   University of Göttingen

   Affiliation as printed

   University of Göttingen, Göttingen Center for Molecular Biology, Göttingen, Germany

5. Olivia Cracknell

   Babraham Institute

   Affiliation as printed

   Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK

6. Tim Lohoff

   Babraham Institute

   Affiliation as printed

   Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK

   Forbian, Gaertnerplatz 6, Munich, Germany

7. Ricard Argelaguet

   Babraham Institute · University of Cambridge

   Affiliation as printed

   Altos Labs Cambridge Institute of Science, Granta Park, Cambridge, UK

   Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK

8. Juliette Pearce Aachen Institute for Cell and Tumor Biology

   Babraham Institute · Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK

   Institute for Cell and Tumor Biology, RWTH Aachen University Hospital, Aachen, Germany

9. Ioannis Kafetzopoulos

   Babraham Institute · University of Cambridge

   Affiliation as printed

   Altos Labs Cambridge Institute of Science, Granta Park, Cambridge, UK

   Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK

10. Alice Santambrogio

    Babraham Institute · University of Cambridge

    Affiliation as printed

    Altos Labs Cambridge Institute of Science, Granta Park, Cambridge, UK

    Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK

11. Jennifer Nichols

    Wellcome/MRC Cambridge Stem Cell Institute · University of Cambridge · Institute of Genetics and Cancer · University of Edinburgh

    Affiliation as printed

    Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK

    Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK

12. Ferdinand von Meyenn

    Babraham Institute · ETH Zurich

    Affiliation as printed

    Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK

    Laboratory of Nutrition and Metabolic Epigenetics, ETH Zurich, Zurich, Switzerland

13. Ufuk Günesdogan

    University of Göttingen

    Affiliation as printed

    University of Göttingen, Göttingen Center for Molecular Biology, Göttingen, Germany

14. Stefan Schoenfelder corresponding

    Babraham Institute

    Affiliation as printed

    Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK

15. Wolf Reik corresponding

    Babraham Institute · University of Cambridge

    Affiliation as printed

    Altos Labs Cambridge Institute of Science, Granta Park, Cambridge, UK

    Epigenetics Programme, Babraham Institute, Babraham Research Campus, Cambridge, UK