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Clin Epigenetics. 2018 Jul 13;10(1):95. doi: 10.1186/s13148-018-0526-8.

Loss of maternal EED results in postnatal overgrowth.

Author information

1
Centre for Reproductive Health, Hudson Institute of Medical Research and Department of Molecular and Translational Science, Monash University, Clayton, Victoria, 3168, Australia.
2
Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia.
3
Centre for Geometric Biology, School of Biological Sciences, Monash University, Clayton, Victoria, 3800, Australia.
4
Leiden Genome Technology Centre, Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
5
Department of Medical Genetics, University of British Columbia and British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
6
Centre for Reproductive Health, Hudson Institute of Medical Research and Department of Molecular and Translational Science, Monash University, Clayton, Victoria, 3168, Australia. patrick.western@hudson.org.au.

Abstract

BACKGROUND:

Investigating how epigenetic information is transmitted through the mammalian germline is the key to understanding how this information impacts on health and disease susceptibility in offspring. EED is essential for regulating the repressive histone modification, histone 3 lysine 27 tri-methylation (H3K27me3) at many developmental genes.

RESULTS:

In this study, we used oocyte-specific Zp3-Cre recombinase (Zp3Cre) to delete Eed specifically in mouse growing oocytes, permitting the study of EED function in oocytes and the impact of depleting EED in oocytes on outcomes in offspring. As EED deletion occurred only in growing oocytes and females were mated to normal wild type males, this model allowed the study of oocyte programming without confounding factors such as altered in utero environment. Loss of EED from growing oocytes resulted in a significant overgrowth phenotype that persisted into adult life. Significantly, this involved increased adiposity (total fat) and bone mineral density in offspring. Similar overgrowth occurs in humans with Cohen-Gibson (OMIM 617561) and Weaver (OMIM 277590) syndromes, that result from de novo germline mutations in EED or its co-factor EZH2, respectively. Consistent with a role for EZH2 in human oocytes, we demonstrate that de novo germline mutations in EZH2 occurred in the maternal germline in some cases of Weaver syndrome. However, deletion of Ezh2 in mouse oocytes resulted in a distinct phenotype compared to that resulting from oocyte-specific deletion of Eed.

CONCLUSIONS:

This study provides novel evidence that altering EED-dependent oocyte programming leads to compromised offspring growth and development in the next generation.

KEYWORDS:

EED; EZH2; Epigenetic inheritance; Germ; H3K27me3; Histone; Oocyte; Overgrowth; Polycomb; Weaver

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