Molecular Cell
Volume 81, Issue 8, 15 April 2021, Pages 1732-1748.e8
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Article
H3K27ac bookmarking promotes rapid post-mitotic activation of the pluripotent stem cell program without impacting 3D chromatin reorganization

https://doi.org/10.1016/j.molcel.2021.02.032Get rights and content
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Highlights

  • Rapid resetting of the stem cell program and transient activation of lineage genes

  • Chromatin contacts around stem cells enhancers reform faster than structural loops

  • Chromatin reorganization partially associates with transcriptional levels and kinetics

  • Loss of mitotic H3K27ac perturbs transcriptional but not architectural resetting

Summary

During self-renewal, cell-type-defining features are drastically perturbed in mitosis and must be faithfully reestablished upon G1 entry, a process that remains largely elusive. Here, we characterized at a genome-wide scale the dynamic transcriptional and architectural resetting of mouse pluripotent stem cells (PSCs) upon mitotic exit. We captured distinct waves of transcriptional reactivation with rapid induction of stem cell genes and transient activation of lineage-specific genes. Topological reorganization at different hierarchical levels also occurred in an asynchronous manner and showed partial coordination with transcriptional resetting. Globally, rapid transcriptional and architectural resetting associated with mitotic retention of H3K27 acetylation, supporting a bookmarking function. Indeed, mitotic depletion of H3K27ac impaired the early reactivation of bookmarked, stem-cell-associated genes. However, 3D chromatin reorganization remained largely unaffected, suggesting that these processes are driven by distinct forces upon mitotic exit. This study uncovers principles and mediators of PSC molecular resetting during self-renewal.

Keywords

mitosis
pluripotent stem cells
transcription reactivation
3D chromatin organization
bookmarking
H3K27ac
enhancer-promoter interaction
cell identity
PRO-seq
Hi-C

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These authors contributed equally

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