Article

Programming asynchronous replication in stem cells

  • Nature Structural & Molecular Biology volume 24, pages 11321138 (2017)
  • doi:10.1038/nsmb.3503
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Abstract

Many regions of the genome replicate asynchronously and are expressed monoallelically. It is thought that asynchronous replication may be involved in choosing one allele over the other, but little is known about how these patterns are established during development. We show that, unlike somatic cells, which replicate in a clonal manner, embryonic and adult stem cells are programmed to undergo switching, such that daughter cells with an early-replicating paternal allele are derived from mother cells that have a late-replicating paternal allele. Furthermore, using ground-state embryonic stem (ES) cells, we demonstrate that in the initial transition to asynchronous replication, it is always the paternal allele that is chosen to replicate early, suggesting that primary allelic choice is directed by preset gametic DNA markers. Taken together, these studies help define a basic general strategy for establishing allelic discrimination and generating allelic diversity throughout the organism.

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Acknowledgements

We thank N. Grover for statistical analyses, J. Hannah (Weizmann Institute, Rehovot, Israel) for providing the BiPS cells and M. Berger for help with FACS sorting. This work was supported by research grants from the Israel Academy of Sciences (grant 419/10 to H.C., grant 734/13 to Y.B.), the Israel Cancer Research Foundation (grant 210910 to H.C., grant 211410 to Y.B.), The Binational Science Foundation (grant 2100289 to Y.B.), The Emanuel Rubin Chair in Medical Sciences (Y.B.), the European Research Council (grant 268614 to H.C.), Rosetrees Foundation (H.C.), the Israel Centers of Excellence Program (41/11 to H.C., grant 1796/12 to Y.B.) and Lew Sanders (H.C.).

Author information

Author notes

    • Hagit Masika
    •  & Marganit Farago

    These authors contributed equally to this work.

    • Yehudit Bergman
    •  & Howard Cedar

    These authors jointly directed this work.

Affiliations

  1. Department of Developmental Biology and Cancer Research, Hebrew University Medical School, Jerusalem, Israel.

    • Hagit Masika
    • , Marganit Farago
    • , Merav Hecht
    • , Reba Condiotti
    • , Kirill Makedonski
    • , Yosef Buganim
    • , Yehudit Bergman
    •  & Howard Cedar
  2. The Institute of Dental Sciences, Faculty of Dental Medicine, Hebrew University–Hadassah, Jerusalem, Israel.

    • Tal Burstyn-Cohen

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Contributions

H.M. and M.F. designed and conducted the experiments, interpreted the results and assisted in manuscript preparation. M.H. validated the replication timing data by ReTiSH analysis. R.C. generated the mammospheres, K.M. and Y. Buganim generated ES lines 11 and 12 and assisted in generating the EpiSCs, T.B.-C. generated the neurospheres and assisted in designing methods for the other spheroids. H.C. and Y. Bergman directed the study and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yehudit Bergman.

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