Dynamic changes in replication timing and gene expression during lineage specification of human pluripotent stem cells
- Juan Carlos Rivera-Mulia1,
- Quinton Buckley1,
- Takayo Sasaki1,
- Jared Zimmerman1,
- Ruth A. Didier2,
- Kristopher Nazor3,
- Jeanne F. Loring3,
- Zheng Lian4,
- Sherman Weissman4,
- Allan J. Robins5,
- Thomas C. Schulz5,
- Laura Menendez6,
- Michael J. Kulik6,
- Stephen Dalton6,
- Haitham Gabr7,
- Tamer Kahveci7 and
- David M. Gilbert1,8
- 1Department of Biological Science, Florida State University, Tallahassee, Florida 32306-4295, USA;
- 2College of Medicine, Florida State University, Tallahassee, Florida 32306-4295, USA;
- 3Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA;
- 4Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06519, USA;
- 5ViaCyte, Inc., Athens, Georgia 30602, USA;
- 6Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602, USA;
- 7Department of Computer and Information Sciences and Engineering, University of Florida, Gainesville, Florida 32611, USA;
- 8Center for Genomics and Personalized Medicine, Florida State University, Tallahassee, Florida 32306, USA
- Corresponding author: gilbert{at}bio.fsu.edu
Abstract
Duplication of the genome in mammalian cells occurs in a defined temporal order referred to as its replication-timing (RT) program. RT changes dynamically during development, regulated in units of 400–800 kb referred to as replication domains (RDs). Changes in RT are generally coordinated with transcriptional competence and changes in subnuclear position. We generated genome-wide RT profiles for 26 distinct human cell types, including embryonic stem cell (hESC)-derived, primary cells and established cell lines representing intermediate stages of endoderm, mesoderm, ectoderm, and neural crest (NC) development. We identified clusters of RDs that replicate at unique times in each stage (RT signatures) and confirmed global consolidation of the genome into larger synchronously replicating segments during differentiation. Surprisingly, transcriptome data revealed that the well-accepted correlation between early replication and transcriptional activity was restricted to RT-constitutive genes, whereas two-thirds of the genes that switched RT during differentiation were strongly expressed when late replicating in one or more cell types. Closer inspection revealed that transcription of this class of genes was frequently restricted to the lineage in which the RT switch occurred, but was induced prior to a late-to-early RT switch and/or down-regulated after an early-to-late RT switch. Analysis of transcriptional regulatory networks showed that this class of genes contains strong regulators of genes that were only expressed when early replicating. These results provide intriguing new insight into the complex relationship between transcription and RT regulation during human development.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.187989.114.
- Received December 2, 2014.
- Accepted June 5, 2015.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
