Abstract
The temporal order of DNA replication is regulated during development and is highly correlated with gene expression, histone modifications and 3D genome architecture. We tracked changes in replication timing, gene expression, and chromatin conformation capture (Hi-C) A/B compartments over the first two cell cycles during differentiation of human embryonic stem cells to definitive endoderm. Remarkably, transcriptional programs were irreversibly reprogrammed within the first cell cycle and were largely but not universally coordinated with replication timing changes. Moreover, changes in A/B compartment and several histone modifications that normally correlate strongly with replication timing showed weak correlation during the early cell cycles of differentiation but showed increased alignment in later differentiation stages and in terminally differentiated cell lines. Thus, epigenetic cell fate transitions during early differentiation can occur despite dynamic and discordant changes in otherwise highly correlated genomic properties. The temporal order of DNA replication is regulated during development, and is highly correlated with gene expression, chromatin structure, and 3D-genome architecture. Gilbert and colleagues find that stable transcriptional changes of human embryonic stem cells to endoderm can occur within a single cell cycle, accompanied by discordance in replication timing and chromatin compartment that align in later differentiation stages.
Original language | English (US) |
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Pages (from-to) | 193-206 |
Number of pages | 14 |
Journal | Stem Cell Reports |
Volume | 13 |
Issue number | 1 |
DOIs | |
State | Published - Jul 9 2019 |
Externally published | Yes |
Bibliographical note
Funding Information:We thank R. Didier for assistance with flow cytometry. This work was funded by NIH grants GM085354 and GM083337 to D.M.G. and HG003143 to J.D. A.J.R. and T.C.S. are employees of Viacyte receiving salary and stock options.
Funding Information:
We thank R. Didier for assistance with flow cytometry. This work was funded by NIH grants GM085354 and GM083337 to D.M.G. and HG003143 to J.D. A.J.R. and T.C.S. are employees of Viacyte receiving salary and stock options.
Publisher Copyright:
© 2019 The Author(s)
Keywords
- chromatin 3D architecture
- chromatin 3D organization
- chromatin structure
- differentiation
- gene expression
- lineage commitment
- replication timing