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Incomplete Reprogramming of DNA Replication Timing in Induced Pluripotent Stem Cells
Matthew M Edwards1, Ning Wang2,3, Dashiell J Massey1
1Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA.
Biorxiv : the Preprint Server for Biology
|July 3, 2023
Summary
Induced pluripotent stem cells (iPSCs) show altered DNA replication timing compared to embryonic stem cells (ESCs). This timing issue, linked to gene regulation, can persist and affect iPSC quality for cell therapy.
Area of Science:
- Stem cell biology
- Genomics
- Epigenetics
Background:
- Induced pluripotent stem cells (iPSCs) are crucial for cell therapy, but their genomic state compared to embryonic stem cells (ESCs) requires thorough evaluation.
- While differences in gene expression and DNA methylation are known, the reprogramming efficiency of DNA replication timing in iPSCs remains largely unexplored.
Approach:
- Genome-wide replication timing was profiled and compared between ESCs, iPSCs, and nuclear transfer-derived ESCs (NT-ESCs).
- Analysis focused on identifying discrepancies in DNA replication patterns and their correlation with epigenetic modifications and gene expression.
Key Points:
- NT-ESCs exhibited DNA replication timing indistinguishable from ESCs.
- A subset of iPSCs displayed delayed DNA replication in heterochromatic regions, associated with downregulated genes and incomplete DNA methylation reprogramming.
- These replication timing delays were independent of gene expression and DNA methylation changes and persisted through neuronal differentiation.
Conclusions:
- DNA replication timing is a genomic feature that can be resistant to reprogramming in iPSCs.
- Replication timing abnormalities may lead to undesirable phenotypes, highlighting its importance in evaluating iPSC line quality for therapeutic applications.
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