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

Yaser Atlasi, Wout Megchelenbrink, Tianran Peng, Ehsan Habibi, Onkar Joshi, Shuang-Yin Wang, Cheng Wang, Colin Logie, Ina Poser, Hendrik Marks, Hendrik G Stunnenberg

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)568-578
Number of pages11
JournalNature Cell Biology
Issue number5
Publication statusPublished - 29 Apr 2019
Externally publishedYes


  • Animals
  • CRISPR-Cas Systems/genetics
  • Cell Differentiation/genetics
  • Chromatin/genetics
  • Enhancer Elements, Genetic
  • Epigenesis, Genetic
  • Histones/genetics
  • Mice
  • Mouse Embryonic Stem Cells/metabolism
  • Pluripotent Stem Cells
  • Promoter Regions, Genetic
  • Receptors, Estrogen/genetics
  • Transcriptome/genetics


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