Fetal growth delay caused by loss of non-canonical imprinting is resolved late in pregnancy and culminates in offspring overgrowth

  1. Ruby Oberin
  2. Sigrid Petautschnig
  3. Ellen G Jarred
  4. Zhipeng Qu
  5. Tesha Tsai Ph.D.
  6. Neil A Youngson
  7. Gabrielle Pulsoni
  8. Thi T Truong
  9. Dilini Fernando
  10. Heidi Bildsoe Ph.D.
  11. Rheannon O Blucher
  12. Maarten van den Buuse
  13. David K Gardner
  14. Natalie A Sims
  15. David Louis Adelson
  16. Patrick S Western  Is a corresponding author
  1. Monash University, Australia
  2. University of Adelaide, Australia
  3. University of Melbourne, Australia
  4. La Trobe University, Australia
  5. St. Vincent's Hospital, Australia

Abstract

Germline epigenetic programming, including genomic imprinting, substantially influences offspring development. Polycomb Repressive Complex 2 (PRC2) plays an important role in Histone 3 Lysine 27 trimethylation (H3K27me3)-dependent imprinting, loss of which leads to growth and developmental changes in mouse offspring. In this study, we show that offspring from mouse oocytes lacking the PRC2 protein Embryonic Ectoderm Development (EED) were initially developmentally delayed, characterised by low blastocyst cell counts and substantial growth delay in mid-gestation embryos. This initial developmental delay was resolved as offspring underwent accelerated fetal development and growth in late gestation resulting in offspring that were similar stage and weight to controls at birth. The accelerated development and growth in offspring from Eed-null oocytes was associated with remodelling of the placenta, which involved an increase in fetal and maternal tissue size, conspicuous expansion of the glycogen enriched cell population and delayed parturition. Despite placental remodelling and accelerated offspring fetal growth and development, placental efficiency and fetal blood glucose levels were low, and the fetal blood metabolome was unchanged. Moreover, while expression of the H3K27me3-imprinted gene and amino acid transporter Slc38a4 was increased, fetal blood levels of individual amino acids were similar to controls, indicating that placental amino acid transport was not enhanced. Genome-wide analyses identified extensive transcriptional dysregulation and DNA methylation changes in affected placentas, including a range of imprinted and non-imprinted genes. Together, while deletion of Eed in growing oocytes resulted in fetal growth and developmental delay and placental hyperplasia, our data indicate a remarkable capacity for offspring fetal growth to be normalised despite inefficient placental function and the loss of H3K27me3-dependent genomic imprinting.

Data availability

All RNA sequencing and RRBS data have been deposited to the Gene Expression Omnibus (GEO) and are publicly available with accession number GSE210398. The metabolomics data are available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org where it has been assigned Study ID ST003211. The data can be accessed directly via its Project DOI: http://doi.org/10.21228/M8TR5T. Data for Figures 6 and 8 are included in Supplementary file 1.

The following data sets were generated

Article and author information

Author details

  1. Ruby Oberin

    Department of Molecular and Translational Science, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  2. Sigrid Petautschnig

    Department of Molecular and Translational Science, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. Ellen G Jarred

    Department of Molecular and Translational Science, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Zhipeng Qu

    Department of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
  5. Tesha Tsai Ph.D.

    Department of Molecular and Translational Science, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Neil A Youngson

    Department of Molecular and Translational Science, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Gabrielle Pulsoni

    Department of Molecular and Translational Science, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  8. Thi T Truong

    School of BioSciences, University of Melbourne, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Dilini Fernando

    Department of Molecular and Translational Science, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Heidi Bildsoe Ph.D.

    Department of Molecular and Translational Science, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. Rheannon O Blucher

    Department of Molecular and Translational Science, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  12. Maarten van den Buuse

    School of Psychology and Public Health, La Trobe University, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
  13. David K Gardner

    School of BioSciences, University of Melbourne, Melbourne, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3138-8274
  14. Natalie A Sims

    Department of Medicine, St. Vincent's Hospital, Fitzroy, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1421-8468
  15. David Louis Adelson

    Department of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2404-5636
  16. Patrick S Western

    Department of Molecular and Translational Science, Monash University, Clayton, Australia
    For correspondence
    patrick.western@hudson.org.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7587-8227

Funding

National Health and Medical Research Council (1144966)

  • Maarten van den Buuse
  • David K Gardner
  • David Louis Adelson
  • Patrick S Western

National Health and Medical Research Council (1144887)

  • David K Gardner
  • David Louis Adelson
  • Patrick S Western

National Health and Medical Research Council (2021247)

  • David Louis Adelson
  • Patrick S Western

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal work was undertaken in accordance with Monash University Animal Ethics Committee (AEC) approvals issued by Monash University and Hudson Institute Animal Ethics Committees (AEC), approval numbers MMCB/2018/16 and MMCB/2020/37

Copyright

© 2024, Oberin 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. Ruby Oberin
  2. Sigrid Petautschnig
  3. Ellen G Jarred
  4. Zhipeng Qu
  5. Tesha Tsai Ph.D.
  6. Neil A Youngson
  7. Gabrielle Pulsoni
  8. Thi T Truong
  9. Dilini Fernando
  10. Heidi Bildsoe Ph.D.
  11. Rheannon O Blucher
  12. Maarten van den Buuse
  13. David K Gardner
  14. Natalie A Sims
  15. David Louis Adelson
  16. Patrick S Western
(2024)
Fetal growth delay caused by loss of non-canonical imprinting is resolved late in pregnancy and culminates in offspring overgrowth
eLife 13:e81875.
https://doi.org/10.7554/eLife.81875

Share this article

https://doi.org/10.7554/eLife.81875

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