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Physiological re-replication during human stem cell differentiation
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DOI：10.1038/s41420-026-03267-9.png)
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Abstract
En 中文
During restricted timeframes in Drosophila development, re-replication occurs as physiological process causing the known developmental gene amplification in Drosophila. Gene amplification has also been found during differentiation in human stem cells but re-replication in human cells has been preferentially associated with tumor related genome instability. Here, we show that re-replication also occurs as physiological process in human stem cells. We used Rerep-Seq and fiber-combing to demonstrate re-replication during the differentiation of human myoblasts into myotubes and during the differentiation of mesenchymal stem cells into adipocytes, osteoblasts, chondrocytes, and neurons. Re-replication was detectable during specific timeframes in all differentiations analyzed. FACS sorting of re-replicating cells showed increased gene expression in re-replicated genome regions. Additionally, re-replicated DNA was identified as extranuclear DNA. This leads us to the hypothesis that cells that do not re-replicate and thus do not face an increased risk of chromosomal instability may ensure higher expression of certain genes and their encoded proteins during differentiation by incorporating re-replicated DNA from neighbouring cells with re-replication. We propose that human stem cells use an ancient re-replication mechanism to efficiently increase gene copy numbers, thereby meeting the heightened protein demands during differentiation.
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