1. Developmental Biology
  2. Chromosomes and Gene Expression

Chromatin dynamics and the role of G9a in gene regulation and enhancer silencing during early mouse development

  1. Jan J Zylicz
  2. Sabine Dietmann
  3. Ufuk Günesdogan
  4. Jamie A Hackett
  5. Delphine Cougot
  6. Caroline Lee
  7. M Azim Surani  Is a corresponding author
  1. University of Cambridge, United Kingdom
https://doi.org/10.7554/eLife.09571
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Cite this article
  1. Jan J Zylicz
  2. Sabine Dietmann
  3. Ufuk Günesdogan
  4. Jamie A Hackett
  5. Delphine Cougot
  6. Caroline Lee
  7. M Azim Surani
(2015)
Chromatin dynamics and the role of G9a in gene regulation and enhancer silencing during early mouse development
eLife 4:e09571.
https://doi.org/10.7554/eLife.09571
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Abstract

Early mouse development is accompanied by dynamic changes in chromatin modifications, including G9a-mediated histone H3 lysine 9 dimethylation (H3K9me2), which is essential for embryonic development. Here we show that genome-wide accumulation of H3K9me2 is crucial for postimplantation development, and coincides with redistribution of EZH2-dependent histone H3 lysine 27 trimethylation (H3K27me3). Loss of G9a or EZH2 results in upregulation of distinct gene sets involved in cell cycle regulation, germline development and embryogenesis. Notably, the H3K9me2 modification extends to active enhancer elements where it promotes developmentally-linked gene silencing and directly marks promoters and gene bodies. This epigenetic mechanism is important for priming gene regulatory networks for critical cell fate decisions in rapidly proliferating postimplantation epiblast cells.

Article and author information

Author details

  1. Jan J Zylicz

    Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Sabine Dietmann

    Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  3. Ufuk Günesdogan

    Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  4. Jamie A Hackett

    Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Delphine Cougot

    Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Caroline Lee

    Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  7. M Azim Surani

    Wellcome Trust / Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    a.surani@gurdon.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Asifa Akhtar, Max Planck Institute for Immunobiology and Epigenetics, Germany

Ethics

Animal experimentation: All husbandry and experiments involving mice were authorized by a UK Home Office Project License 80/2637 and carried out in a Home Office-designated facility.

Version history

  1. Received: June 19, 2015
  2. Accepted: November 6, 2015
  3. Accepted Manuscript published: November 9, 2015 (version 1)
  4. Version of Record published: December 9, 2015 (version 2)

Copyright

© 2015, Zylicz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jan J Zylicz
  2. Sabine Dietmann
  3. Ufuk Günesdogan
  4. Jamie A Hackett
  5. Delphine Cougot
  6. Caroline Lee
  7. M Azim Surani
(2015)
Chromatin dynamics and the role of G9a in gene regulation and enhancer silencing during early mouse development
eLife 4:e09571.
https://doi.org/10.7554/eLife.09571

Share this article

https://doi.org/10.7554/eLife.09571

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Further reading

    1. Chromosomes and Gene Expression
    2. Developmental Biology

    G9a regulates temporal preimplantation developmental program and lineage segregation in blastocyst

    Jan J Zylicz, Maud Borensztein ... M Azim Surani
    Research Advance Updated

    Early mouse development is regulated and accompanied by dynamic changes in chromatin modifications, including G9a-mediated histone H3 lysine 9 dimethylation (H3K9me2). Previously, we provided insights into its role in post-implantation development (Zylicz et al., 2015). Here we explore the impact of depleting the maternally inherited G9a in oocytes on development shortly after fertilisation. We show that G9a accumulates typically at 4 to 8 cell stage to promote timely repression of a subset of 4 cell stage-specific genes. Loss of maternal inheritance of G9a disrupts the gene regulatory network resulting in developmental delay and destabilisation of inner cell mass lineages by the late blastocyst stage. Our results indicate a vital role of this maternally inherited epigenetic regulator in creating conducive conditions for developmental progression and on cell fate choices.

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    Morphogenesis: The enigma of cell intercalation

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    Geometric criteria can be used to assess whether cell intercalation is active or passive during the convergent extension of tissue.

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    The MODY-associated KCNK16 L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

    Arya Y Nakhe, Prasanna K Dadi ... David A Jacobson
    Research Article

    The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.