Pharmacological inhibition of EZH2 disrupts the female germline epigenome

Lexie Prokopuk, Kirsten Hogg, Patrick S. Western

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

Background: Recently discovered drugs that target epigenetic modifying complexes are providing new treatment options for a range of cancers that affect patients of reproductive age. Although these drugs provide new therapies, it is likely that they will also affect epigenetic programming in sperm and oocytes. A promising target is Enhancer of Zeste 2 (EZH2), which establishes the essential epigenetic modification, H3K27me3, during development. Results: In this study, we demonstrate that inhibition of EZH1/2 with the clinically relevant drug, tazemetostat, severely depletes H3K27me3 in growing oocytes of adult female mice. Moreover, EZH2 inhibition depleted H3K27me3 in primary oocytes and in fetal oocytes undergoing epigenetic reprogramming. Surprisingly, once depleted, H3K27me3 failed to recover in growing oocytes or in fetal oocytes. Conclusion: Together, these data demonstrate that drugs targeting EZH2 significantly affect the germline epigenome and, based on genetic models with oocyte-specific loss of EZH2 function, are likely to affect outcomes in offspring.

Original languageEnglish
Article number33
Number of pages12
JournalClinical Epigenetics
Volume10
Issue number1
DOIs
Publication statusPublished - 5 Mar 2018

Keywords

  • Epigenetic
  • Germline
  • H3K27me3
  • Inheritance
  • Oocyte
  • Pharmacology
  • PRC2

Cite this

@article{49091604583d4594bf79c487267f8839,
title = "Pharmacological inhibition of EZH2 disrupts the female germline epigenome",
abstract = "Background: Recently discovered drugs that target epigenetic modifying complexes are providing new treatment options for a range of cancers that affect patients of reproductive age. Although these drugs provide new therapies, it is likely that they will also affect epigenetic programming in sperm and oocytes. A promising target is Enhancer of Zeste 2 (EZH2), which establishes the essential epigenetic modification, H3K27me3, during development. Results: In this study, we demonstrate that inhibition of EZH1/2 with the clinically relevant drug, tazemetostat, severely depletes H3K27me3 in growing oocytes of adult female mice. Moreover, EZH2 inhibition depleted H3K27me3 in primary oocytes and in fetal oocytes undergoing epigenetic reprogramming. Surprisingly, once depleted, H3K27me3 failed to recover in growing oocytes or in fetal oocytes. Conclusion: Together, these data demonstrate that drugs targeting EZH2 significantly affect the germline epigenome and, based on genetic models with oocyte-specific loss of EZH2 function, are likely to affect outcomes in offspring.",
keywords = "Epigenetic, Germline, H3K27me3, Inheritance, Oocyte, Pharmacology, PRC2",
author = "Lexie Prokopuk and Kirsten Hogg and Western, {Patrick S.}",
year = "2018",
month = "3",
day = "5",
doi = "10.1186/s13148-018-0465-4",
language = "English",
volume = "10",
journal = "Clinical Epigenetics",
issn = "1868-7075",
publisher = "Springer-Verlag London Ltd.",
number = "1",

}

Pharmacological inhibition of EZH2 disrupts the female germline epigenome. / Prokopuk, Lexie; Hogg, Kirsten; Western, Patrick S.

In: Clinical Epigenetics, Vol. 10, No. 1, 33, 05.03.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pharmacological inhibition of EZH2 disrupts the female germline epigenome

AU - Prokopuk, Lexie

AU - Hogg, Kirsten

AU - Western, Patrick S.

PY - 2018/3/5

Y1 - 2018/3/5

N2 - Background: Recently discovered drugs that target epigenetic modifying complexes are providing new treatment options for a range of cancers that affect patients of reproductive age. Although these drugs provide new therapies, it is likely that they will also affect epigenetic programming in sperm and oocytes. A promising target is Enhancer of Zeste 2 (EZH2), which establishes the essential epigenetic modification, H3K27me3, during development. Results: In this study, we demonstrate that inhibition of EZH1/2 with the clinically relevant drug, tazemetostat, severely depletes H3K27me3 in growing oocytes of adult female mice. Moreover, EZH2 inhibition depleted H3K27me3 in primary oocytes and in fetal oocytes undergoing epigenetic reprogramming. Surprisingly, once depleted, H3K27me3 failed to recover in growing oocytes or in fetal oocytes. Conclusion: Together, these data demonstrate that drugs targeting EZH2 significantly affect the germline epigenome and, based on genetic models with oocyte-specific loss of EZH2 function, are likely to affect outcomes in offspring.

AB - Background: Recently discovered drugs that target epigenetic modifying complexes are providing new treatment options for a range of cancers that affect patients of reproductive age. Although these drugs provide new therapies, it is likely that they will also affect epigenetic programming in sperm and oocytes. A promising target is Enhancer of Zeste 2 (EZH2), which establishes the essential epigenetic modification, H3K27me3, during development. Results: In this study, we demonstrate that inhibition of EZH1/2 with the clinically relevant drug, tazemetostat, severely depletes H3K27me3 in growing oocytes of adult female mice. Moreover, EZH2 inhibition depleted H3K27me3 in primary oocytes and in fetal oocytes undergoing epigenetic reprogramming. Surprisingly, once depleted, H3K27me3 failed to recover in growing oocytes or in fetal oocytes. Conclusion: Together, these data demonstrate that drugs targeting EZH2 significantly affect the germline epigenome and, based on genetic models with oocyte-specific loss of EZH2 function, are likely to affect outcomes in offspring.

KW - Epigenetic

KW - Germline

KW - H3K27me3

KW - Inheritance

KW - Oocyte

KW - Pharmacology

KW - PRC2

UR - http://www.scopus.com/inward/record.url?scp=85043346027&partnerID=8YFLogxK

U2 - 10.1186/s13148-018-0465-4

DO - 10.1186/s13148-018-0465-4

M3 - Article

AN - SCOPUS:85043346027

VL - 10

JO - Clinical Epigenetics

JF - Clinical Epigenetics

SN - 1868-7075

IS - 1

M1 - 33

ER -