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.
Original language | English |
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Pages (from-to) | 568-578 |
Number of pages | 11 |
Journal | Nature Cell Biology |
Volume | 21 |
Issue number | 5 |
DOIs | |
Publication status | Published - 29 Apr 2019 |
Externally published | Yes |
Keywords
- 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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Yaser Atlasi
- School of Medicine, Dentistry and Biomedical Sciences - Vice-Chancellor Illuminate Fellow
- Patrick G Johnston Centre for Cancer Research
Person: Research