Loss of maternal EED results in postnatal overgrowth

Lexie Prokopuk, Jessica M. Stringer, Craig R. White, Rolf H.A.M. Vossen, Stefan J. White, Ana S.A. Cohen, William T. Gibson, Patrick S. Western

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Article number95
Number of pages14
JournalClinical Epigenetics
Volume10
Issue number1
DOIs
Publication statusPublished - 13 Jul 2018

Keywords

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

Cite this

Prokopuk, Lexie ; Stringer, Jessica M. ; White, Craig R. ; Vossen, Rolf H.A.M. ; White, Stefan J. ; Cohen, Ana S.A. ; Gibson, William T. ; Western, Patrick S. / Loss of maternal EED results in postnatal overgrowth. In: Clinical Epigenetics. 2018 ; Vol. 10, No. 1.
@article{6fd3c97a8e014dada53899e8825a35d5,
title = "Loss of maternal EED results in postnatal overgrowth",
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, Epigenetic inheritance, EZH2, Germ, H3K27me3, Histone, Oocyte, Overgrowth, Polycomb, Weaver",
author = "Lexie Prokopuk and Stringer, {Jessica M.} and White, {Craig R.} and Vossen, {Rolf H.A.M.} and White, {Stefan J.} and Cohen, {Ana S.A.} and Gibson, {William T.} and Western, {Patrick S.}",
year = "2018",
month = "7",
day = "13",
doi = "10.1186/s13148-018-0526-8",
language = "English",
volume = "10",
journal = "Clinical Epigenetics",
issn = "1868-7075",
publisher = "Springer-Verlag London Ltd.",
number = "1",

}

Loss of maternal EED results in postnatal overgrowth. / Prokopuk, Lexie; Stringer, Jessica M.; White, Craig R.; Vossen, Rolf H.A.M.; White, Stefan J.; Cohen, Ana S.A.; Gibson, William T.; Western, Patrick S.

In: Clinical Epigenetics, Vol. 10, No. 1, 95, 13.07.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Loss of maternal EED results in postnatal overgrowth

AU - Prokopuk, Lexie

AU - Stringer, Jessica M.

AU - White, Craig R.

AU - Vossen, Rolf H.A.M.

AU - White, Stefan J.

AU - Cohen, Ana S.A.

AU - Gibson, William T.

AU - Western, Patrick S.

PY - 2018/7/13

Y1 - 2018/7/13

N2 - 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.

AB - 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.

KW - EED

KW - Epigenetic inheritance

KW - EZH2

KW - Germ

KW - H3K27me3

KW - Histone

KW - Oocyte

KW - Overgrowth

KW - Polycomb

KW - Weaver

UR - http://www.scopus.com/inward/record.url?scp=85050023880&partnerID=8YFLogxK

U2 - 10.1186/s13148-018-0526-8

DO - 10.1186/s13148-018-0526-8

M3 - Article

VL - 10

JO - Clinical Epigenetics

JF - Clinical Epigenetics

SN - 1868-7075

IS - 1

M1 - 95

ER -