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Nat Cell Biol. 2019 May;21(5):568-578. doi: 10.1038/s41556-019-0310-9. Epub 2019 Apr 29.

Epigenetic modulation of a hardwired 3D chromatin landscape in two naive states of pluripotency.

Author information

1
Department of Molecular Biology, Faculty of Science, Radboud University, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
2
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3
Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
4
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
5
Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
6
Department of Molecular Biology, Faculty of Science, Radboud University, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands. h.stunnenberg@ncmls.ru.nl.

Abstract

The mechanisms underlying enhancer activation and the extent to which enhancer-promoter rewiring contributes to spatiotemporal gene expression are not well understood. Using integrative and time-resolved analyses we show that the extensive transcriptome and epigenome resetting during the conversion between 'serum' and '2i' states of mouse embryonic stem cells (ESCs) takes place with minimal enhancer-promoter rewiring that becomes more evident in primed-state pluripotency. Instead, differential gene expression is strongly linked to enhancer activation via H3K27ac. Conditional depletion of transcription factors and allele-specific enhancer analysis reveal an essential role for Esrrb in H3K27 acetylation and activation of 2i-specific enhancers. Restoration of a polymorphic ESRRB motif using CRISPR-Cas9 in a hybrid ESC line restores ESRRB binding and enhancer H3K27ac in an allele-specific manner but has no effect on chromatin interactions. Our study shows that enhancer activation in serum- and 2i-ESCs is largely driven by transcription factor binding and epigenetic marking in a hardwired network of chromatin interactions.

PMID:
31036938
DOI:
10.1038/s41556-019-0310-9
[Indexed for MEDLINE]

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