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Lsh is required for meiotic chromosome synapsis and retrotransposon silencing in female germ cells

Nature Cell Biology volume 8, pages 1448–1454 (2006)Cite this article

Abstract

Lymphoid specific helicase (Lsh) is a major epigenetic regulator that is essential for DNA methylation and transcriptional silencing of parasitic elements in the mammalian genome1,2. However, whether Lsh is involved in the regulation of chromatin-mediated processes during meiosis is not known. Here, we show that Lsh is essential for the completion of meiosis and transcriptional repression of repetitive elements in the female gonad. Oocytes from Lsh knockout mice exhibit demethylation of transposable elements and tandem repeats at pericentric heterochromatin, as well as incomplete chromosome synapsis associated with persistent RAD51 foci and γH2AX phosphorylation. Failure to load crossover-associated foci results in the generation of non-exchange chromosomes. The severe oocyte loss observed and lack of ovarian follicle formation, together with the patterns of Lsh nuclear compartmentalization in the germ line, demonstrate that Lsh has a critical and previously unidentified role in epigenetic gene silencing and maintenance of genomic stability during female meiosis.

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Figure 1: Lack of oocyte development after culture of Lsh−/− fetal ovaries.
Figure 2: Incomplete chromosome synapsis in pachytene stage Lsh−/− oocytes.
Figure 3: Failure to load crossover-associated foci into fully synapsed bivalents in Lsh-null oocytes.
Figure 4: Evidence for the presence of non-homologous interactions on the X chromosome in Lsh−/− oocytes and quantitative analysis of meiosis-specific and recombination-associated genes.
Figure 5: Abnormal DNA methylation of tandem repeats at centromeric heterochromatin and dispersed IAP elements in Lsh-deficient oocytes.

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Acknowledgements

We thank C. Heyting, C. Hoog, R. Benavente and B. Earnshaw for generous gifts of antibodies, and M. M. Viveiros for helpful comments during manuscript preparation. This research was supported by a grant from the National Institute of Child Health and Human Development (NICHD) National Institutes of Health (NIH; HD042740) to R.D.L.F. and by NIH grant (RR17359) to I.D. This project has been funded in part with Federal funds from the National Cancer Institute (NCI), NIH, under Contract No. N01-C0-12400 to K.M. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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Authors and Affiliations

  1. Department of Clinical Studies, Female Germ Cell Biology Group, Center for Animal Transgenesis and Germ Cell Research, School of Veterinary Medicine, University of Pennsylvania, New Bolton Center, 382 West Street Road, Kennett Square, 19348, PA, USA

    Rabindranath De La Fuente & Claudia Baumann

  2. Department of Clinical Studies, Male Germ Cell Biology Group, Center for Animal Transgenesis and Germ Cell Research, School of Veterinary Medicine, University of Pennsylvania, New Bolton Center, 382 West Street Road, Kennett Square, 19348, PA, USA

    Ina Dobrinski

  3. Laboratory of Molecular Immunoregulation, SAIC-Basic Research Program, National Cancer Institute, Frederick, 21701, MD, USA

    Tao Fan, Anja Schmidtmann & Kathrin Muegge

Authors
  1. Rabindranath De La Fuente
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  2. Claudia Baumann
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  3. Tao Fan
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  6. Kathrin Muegge
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Contributions

This study was designed, overseen and written by R.D.L.F. Analyses of gene expression and DNA methylation were conducted by C.B. Analysis of meiotic configurations and germ-cell culture were conducted by R.D.L.F. T.F. and A.S. conducted the sample collection and genotyping. I.D. contributed to project planning and a critical review of the manuscript. K.M. generated the transgenic mouse strain and contributed to the writing of the manuscript.

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Correspondence to Rabindranath De La Fuente.

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The authors declare no competing financial interests.

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Supplementary figures S1, S2, S3 and S4 (PDF 477 kb)

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De La Fuente, R., Baumann, C., Fan, T. et al. Lsh is required for meiotic chromosome synapsis and retrotransposon silencing in female germ cells. Nat Cell Biol 8, 1448–1454 (2006). https://doi.org/10.1038/ncb1513

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