H3K27ac bookmarking promotes rapid post-mitotic activation of the pluripotent stem cell program without impacting 3D chromatin reorganization

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...

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Bibliographic Details
Published in:Molecular cell 2021-04, Vol.81 (8), p.1732-1748.e8
Main Authors: Pelham-Webb, Bobbie, Polyzos, Alexander, Wojenski, Luke, Kloetgen, Andreas, Li, Jiexi, Di Giammartino, Dafne Campigli, Sakellaropoulos, Theodore, Tsirigos, Aristotelis, Core, Leighton, Apostolou, Effie
Format: Article
Language:English
Subjects:
3D chromatin organization
Acetylation
Animals
bookmarking
cell identity
Cell Line
Chromatin - genetics
Drosophila - genetics
enhancer-promoter interaction
H3K27ac
Hi-C
Histone Code - genetics
Histones - genetics
Male
Mice
Mice, Inbred C57BL
mitosis
Mitosis - genetics
pluripotent stem cells
Pluripotent Stem Cells - physiology
PRO-seq
transcription reactivation
Transcription, Genetic - genetics
Transcriptional Activation - genetics
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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. [Display omitted] •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 Pelham-Webb et al. characterize the kinetics of transcriptional reactivation and 3D chromatin reorganization in pluripotent stem cells after cell division and examine the degree of coordination between these processes. Furthermore, they interrogate the role of mitotic bookmarking factors in the rapid molecular resetting of stem cell identity.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2021.02.032