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Chromosome-specific nonrandom sister chromatid segregation during stem-cell division

Nature volume 498, pages 251–254 (2013)Cite this article

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Abstract

Adult stem cells undergo asymmetric cell division to self-renew and give rise to differentiated cells that comprise mature tissue1. Sister chromatids may be distinguished and segregated nonrandomly in asymmetrically dividing stem cells2, although the underlying mechanism and the purpose it may serve remain elusive. Here we develop the CO-FISH (chromosome orientation fluorescence in situ hybridization) technique3 with single-chromosome resolution and show that sister chromatids of X and Y chromosomes, but not autosomes, are segregated nonrandomly during asymmetric divisions of Drosophila male germline stem cells. This provides the first direct evidence, to our knowledge, that two sister chromatids containing identical genetic information can be distinguished and segregated nonrandomly during asymmetric stem-cell divisions. We further show that the centrosome, SUN–KASH nuclear envelope proteins and Dnmt2 (also known as Mt2) are required for nonrandom sister chromatid segregation. Our data indicate that the information on X and Y chromosomes that enables nonrandom segregation is primed during gametogenesis in the parents. Moreover, we show that sister chromatid segregation is randomized in germline stem cell overproliferation and dedifferentiated germline stem cells. We propose that nonrandom sister chromatid segregation may serve to transmit distinct information carried on two sister chromatids to the daughters of asymmetrically dividing stem cells.

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Figure 1: Nonrandom segregation of Y and X chromosome strands during GSC divisions.
Figure 2: Autosomes are randomly segregated during GSC divisions.
Figure 3: cnn, koi and klar are required for nonrandom sister chromatid segregation.
Figure 4: Nonrandom segregation of Y and X chromosomes is disrupted in upd-overexpressing testes and dedifferentiated stem cells.

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References

  1. Morrison, S. J. & Kimble, J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441, 1068–1074 (2006)

    Article  ADS  CAS  Google Scholar 

  2. Tajbakhsh, S. & Gonzalez, C. Biased segregation of DNA and centrosomes: moving together or drifting apart? Nature Rev. Mol. Cell Biol. 10, 804–810 (2009)

    Article  CAS  Google Scholar 

  3. Falconer, E. et al. Identification of sister chromatids by DNA template strand sequences. Nature 463, 93–97 (2010)

    Article  ADS  CAS  Google Scholar 

  4. Fuller, M. T. & Spradling, A. C. Male and female Drosophila germline stem cells: two versions of immortality. Science 316, 402–404 (2007)

    Article  ADS  CAS  Google Scholar 

  5. Yamashita, Y. M., Jones, D. L. & Fuller, M. T. Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 301, 1547–1550 (2003)

    Article  ADS  CAS  Google Scholar 

  6. Yamashita, Y. M., Mahowald, A. P., Perlin, J. R. & Fuller, M. T. Asymmetric inheritance of mother versus daughter centrosome in stem cell division. Science 315, 518–521 (2007)

    Article  ADS  CAS  Google Scholar 

  7. Dernburg, A. F. in Drosophila Protocols (eds Sullivan, W., Ashburner, M. & Hawley, R. S.) Ch. 2 (CSHL Press, 2000)

    Google Scholar 

  8. Fung, J. C., Marshall, W. F., Dernburg, A., Agard, D. A. & Sedat, J. W. Homologous chromosome pairing in Drosophila melanogaster proceeds through multiple independent initiations. J. Cell Biol. 141, 5–20 (1998)

    Article  CAS  Google Scholar 

  9. Makunin, I. V. et al. A novel simple satellite DNA is colocalized with the Stalker retrotransposon in Drosophila melanogaster heterochromatin. Mol. Gen. Genet. 261, 381–387 (1999)

    Article  CAS  Google Scholar 

  10. Li, K. & Kaufman, T. C. The homeotic target gene centrosomin encodes an essential centrosomal component. Cell 85, 585–596 (1996)

    Article  CAS  Google Scholar 

  11. Kracklauer, M. P., Banks, S. M., Xie, X., Wu, Y. & Fischer, J. A. Drosophila klaroid encodes a SUN domain protein required for Klarsicht localization to the nuclear envelope and nuclear migration in the eye. Fly (Austin) 1, 75–85 (2007)

    Article  Google Scholar 

  12. Mosley-Bishop, K. L., Li, Q., Patterson, L. & Fischer, J. A. Molecular analysis of the klarsicht gene and its role in nuclear migration within differentiating cells of the Drosophila eye. Curr. Biol. 9, 1211–1220 (1999)

    Article  CAS  Google Scholar 

  13. Razafsky, D. & Hodzic, D. Bringing KASH under the SUN: the many faces of nucleo-cytoskeletal connections. J. Cell Biol. 186, 461–472 (2009)

    Article  CAS  Google Scholar 

  14. Phalke, S. et al. Retrotransposon silencing and telomere integrity in somatic cells of Drosophila depends on the cytosine-5 methyltransferase DNMT2. Nature Genet. 41, 696–702 (2009)

    Article  CAS  Google Scholar 

  15. Kunert, N., Marhold, J., Stanke, J., Stach, D. & Lyko, F. A. Dnmt2-like protein mediates DNA methylation in Drosophila. Development 130, 5083–5090 (2003)

    Article  CAS  Google Scholar 

  16. Schaefer, M. et al. RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes Dev. 24, 1590–1595 (2010)

    Article  CAS  Google Scholar 

  17. Zemach, A., McDaniel, I. E., Silva, P. & Zilberman, D. Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science 328, 916–919 (2010)

    Article  ADS  CAS  Google Scholar 

  18. Brawley, C. & Matunis, E. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 304, 1331–1334 (2004)

    Article  ADS  CAS  Google Scholar 

  19. Kai, T. & Spradling, A. Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries. Nature 428, 564–569 (2004)

    Article  ADS  CAS  Google Scholar 

  20. Cheng, J. et al. Centrosome misorientation reduces stem cell division during ageing. Nature 456, 599–604 (2008)

    Article  ADS  CAS  Google Scholar 

  21. Yadlapalli, S., Cheng, J. & Yamashita, Y. M. Drosophila male germline stem cells do not asymmetrically segregate chromosome strands. J. Cell Sci. 124, 933–939 (2011)

    Article  CAS  Google Scholar 

  22. Conrad, T. & Akhtar, A. Dosage compensation in Drosophila melanogaster: epigenetic fine-tuning of chromosome-wide transcription. Nature Rev. Genet. 13, 123–134 (2012)

    Article  CAS  Google Scholar 

  23. Hense, W., Baines, J. F. & Parsch, J. X chromosome inactivation during Drosophila spermatogenesis. PLoS Biol. 5, e273 (2007)

    Article  Google Scholar 

  24. Aravin, A. A. et al. Double-stranded RNA-mediated silencing of genomic tandem repeats and transposable elements in the D. melanogaster germline. Curr. Biol. 11, 1017–1027 (2001)

    Article  CAS  Google Scholar 

  25. Tulin, A. V., Kogan, G. L., Filipp, D., Balakireva, M. D. & Gvozdev, V. A. Heterochromatic Stellate gene cluster in Drosophila melanogaster: structure and molecular evolution. Genetics 146, 253–262 (1997)

    Article  CAS  Google Scholar 

  26. Tran, V., Lim, C., Xie, J. & Chen, X. Asymmetric division of Drosophila male germline stem cell shows asymmetric histone distribution. Science 338, 679–682 (2012)

    Article  ADS  CAS  Google Scholar 

  27. Minestrini, G., Mathe, E. & Glover, D. M. Domains of the Pavarotti kinesin-like protein that direct its subcellular distribution: effects of mislocalisation on the tubulin and actin cytoskeleton during Drosophila oogenesis. J. Cell Sci. 115, 725–736 (2002)

    Article  CAS  Google Scholar 

  28. Petrella, L. N., Smith-Leiker, T. & Cooley, L. The Ovhts polyprotein is cleaved to produce fusome and ring canal proteins required for Drosophila oogenesis. Development 134, 703–712 (2007)

    Article  CAS  Google Scholar 

  29. Sheng, X. R., Brawley, C. M. & Matunis, E. L. Dedifferentiating spermatogonia outcompete somatic stem cells for niche occupancy in the Drosophila testis. Cell Stem Cell 5, 191–203 (2009)

    Article  CAS  Google Scholar 

  30. Förstemann, K. et al. Normal microRNA maturation and germ-line stem cell maintenance requires Loquacious, a double-stranded RNA-binding domain protein. PLoS Biol. 3, e236 (2005)

    Article  Google Scholar 

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Acknowledgements

We thank F. Lyko, M. Schaefer, G. Reuter, P. Zamore, A. Aravin, D. Glover, L. Cooley, J. Kim, V. Gvozdev, M. Pia Bozzetti, the Bloomington Drosophila Stock Center and the Vienna Drosophila RNAi Center for reagents and helpful information, and Yamashita laboratory members for discussions. This study was supported by the University of Michigan (Life Sciences Institute and Office of the Provost and Executive Vice President for Academic Affairs) (to Y.M.Y.) and AHA (12PRE9630000) and NIH grants (1F31HD071727-01) (to S.Y.). Y.M.Y. is supported by the MacArthur Foundation.

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Authors and Affiliations

  1. Life Sciences Institute, Center for Stem Cell Biology, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Swathi Yadlapalli & Yukiko M. Yamashita

  2. Department of Cell and Developmental Biology, School of Medicine, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Swathi Yadlapalli & Yukiko M. Yamashita

  3. Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Yukiko M. Yamashita

Authors
  1. Swathi Yadlapalli
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Contributions

S.Y. conceived the project and developed the single-chromosome CO-FISH protocol for Drosophila cells. S.Y. and Y.M.Y. designed and conducted experiments, interpreted the data, and wrote the manuscript.

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Correspondence to Swathi Yadlapalli or Yukiko M. Yamashita.

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The authors declare no competing financial interests.

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Yadlapalli, S., Yamashita, Y. Chromosome-specific nonrandom sister chromatid segregation during stem-cell division. Nature 498, 251–254 (2013). https://doi.org/10.1038/nature12106

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