Rapid Irreversible Transcriptional Reprogramming in Human Stem Cells Accompanied by Discordance between Replication Timing and Chromatin Compartment

Vishnu Dileep, Korey A. Wilson, Claire Marchal, Xiaowen Lyu, Peiyao A. Zhao, Ben Li, Axel Poulet, Daniel A. Bartlett, Juan Carlos Rivera-Mulia, Zhaohui S. Qin, Allan J. Robins, Thomas C. Schulz, Michael J. Kulik, Rachel Patton McCord, Job Dekker, Stephen Dalton, Victor G. Corces, David M. Gilbert

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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 languageEnglish (US)
Pages (from-to)193-206
Number of pages14
JournalStem Cell Reports
Volume13
Issue number1
DOIs
StatePublished - Jul 9 2019
Externally publishedYes

Keywords

  • chromatin 3D architecture
  • chromatin 3D organization
  • chromatin structure
  • differentiation
  • gene expression
  • lineage commitment
  • replication timing

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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