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...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-03-01
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| Series: | Clinical Epigenetics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13148-018-0465-4 |
| _version_ | 1819116614602194944 |
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| author | Lexie Prokopuk Kirsten Hogg Patrick S. Western |
| author_facet | Lexie Prokopuk Kirsten Hogg Patrick S. Western |
| author_sort | Lexie Prokopuk |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T05:19:53Z |
| format | Article |
| id | doaj.art-91396ae93ead41f2832b5aaafc8ec844 |
| institution | Directory Open Access Journal |
| issn | 1868-7075 1868-7083 |
| language | English |
| last_indexed | 2024-12-22T05:19:53Z |
| publishDate | 2018-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-91396ae93ead41f2832b5aaafc8ec8442022-12-21T18:37:45ZengBMCClinical Epigenetics1868-70751868-70832018-03-0110111210.1186/s13148-018-0465-4Pharmacological inhibition of EZH2 disrupts the female germline epigenomeLexie Prokopuk0Kirsten Hogg1Patrick S. Western2Centre for Reproductive Health, Hudson Institute of Medical ResearchCentre for Reproductive Health, Hudson Institute of Medical ResearchCentre for Reproductive Health, Hudson Institute of Medical ResearchAbstract 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.http://link.springer.com/article/10.1186/s13148-018-0465-4GermlineOocytePharmacologyEpigeneticPRC2H3K27me3 |
| spellingShingle | Lexie Prokopuk Kirsten Hogg Patrick S. Western Pharmacological inhibition of EZH2 disrupts the female germline epigenome Clinical Epigenetics Germline Oocyte Pharmacology Epigenetic PRC2 H3K27me3 |
| title | Pharmacological inhibition of EZH2 disrupts the female germline epigenome |
| title_full | Pharmacological inhibition of EZH2 disrupts the female germline epigenome |
| title_fullStr | Pharmacological inhibition of EZH2 disrupts the female germline epigenome |
| title_full_unstemmed | Pharmacological inhibition of EZH2 disrupts the female germline epigenome |
| title_short | Pharmacological inhibition of EZH2 disrupts the female germline epigenome |
| title_sort | pharmacological inhibition of ezh2 disrupts the female germline epigenome |
| topic | Germline Oocyte Pharmacology Epigenetic PRC2 H3K27me3 |
| url | http://link.springer.com/article/10.1186/s13148-018-0465-4 |
| work_keys_str_mv | AT lexieprokopuk pharmacologicalinhibitionofezh2disruptsthefemalegermlineepigenome AT kirstenhogg pharmacologicalinhibitionofezh2disruptsthefemalegermlineepigenome AT patrickswestern pharmacologicalinhibitionofezh2disruptsthefemalegermlineepigenome |