1. Developmental Biology
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Maternally provided LSD1/KDM1A enables the maternal-to-zygotic transition and prevents defects that manifest postnatally

  1. Jadiel A Wasson
  2. Ashley K Simon
  3. Dexter A Myrick
  4. Gernot Wolf
  5. Shawn Driscoll
  6. Samuel L Pfaff
  7. Todd S Macfarlan
  8. David J Katz  Is a corresponding author
  1. Emory University School of Medicine, United States
  2. National Institutes of health, United States
  3. Howard Hughes Medical Institute, The Salk Institute for Biological Studies, United States
Research Article
  • Cited 43
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Cite this article as: eLife 2016;5:e08848 doi: 10.7554/eLife.08848

Abstract

Somatic cell nuclear transfer has established that the oocyte contains maternal factors with epigenetic reprogramming capacity. Yet the identity and function of these maternal factors during the gamete to embryo transition remains poorly understood. In C. elegans, LSD1/KDM1A enables this transition by removing H3K4me2 and preventing the transgenerational inheritance of transcription patterns. Here we show that loss of maternal LSD1/KDM1A in mice results in embryonic arrest at the 1-2 cell stage, with arrested embryos failing to undergo the maternal-to-zygotic transition. This suggests that LSD1/KDM1A maternal reprogramming is conserved. Moreover, partial loss of maternal LSD1/KDM1A results in striking phenotypes weeks after fertilization; including perinatal lethality and abnormal behavior in surviving adults. These maternal effect hypomorphic phenotypes are associated with alterations in DNA methylation and expression at imprinted genes. These results establish a novel mammalian paradigm where defects in early epigenetic reprogramming can lead to defects that manifest later in development.

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Author details

  1. Jadiel A Wasson

    Department of Cell Biology, Emory University School of Medicine, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Ashley K Simon

    Department of Human Genetics, Emory University School of Medicine, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Dexter A Myrick

    Department of Cell Biology, Emory University School of Medicine, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Gernot Wolf

    The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Shawn Driscoll

    Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Samuel L Pfaff

    Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Todd S Macfarlan

    The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. David J Katz

    Department of Cell Biology, Emory University School of Medicine, Atlanta, United States
    For correspondence
    djkatz@emory.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All mouse work was performed under the approved guidelines of the Emory University IACUC (protocol #2002534).

Reviewing Editor

  1. Anne C Ferguson-Smith, University of Cambridge, United Kingdom

Publication history

  1. Received: May 21, 2015
  2. Accepted: January 25, 2016
  3. Accepted Manuscript published: January 27, 2016 (version 1)
  4. Version of Record published: April 5, 2016 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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Further reading

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    Maternal LSD1/KDM1A is an essential regulator of chromatin and transcription landscapes during zygotic genome activation

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    Upon fertilization, the highly specialised sperm and oocyte genomes are remodelled to confer totipotency. The mechanisms of the dramatic reprogramming events that occur have remained unknown, and presumed roles of histone modifying enzymes are just starting to be elucidated. Here, we explore the function of the oocyte-inherited pool of a histone H3K4 and K9 demethylase, LSD1/KDM1A during early mouse development. KDM1A deficiency results in developmental arrest by the two-cell stage, accompanied by dramatic and stepwise alterations in H3K9 and H3K4 methylation patterns. At the transcriptional level, the switch of the maternal-to-zygotic transition fails to be induced properly and LINE-1 retrotransposons are not properly silenced. We propose that KDM1A plays critical roles in establishing the correct epigenetic landscape of the zygote upon fertilization, in preserving genome integrity and in initiating new patterns of genome expression that drive early mouse development.

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