Transient Polycomb activity represses developmental genes in growing oocytes

Ellen G Jarred; Zhipeng Qu; Tesha Tsai; Ruby Oberin; Sigrid Petautschnig; Heidi Bildsoe; Stephen Pederson; Qing-Hua Zhang; Jessica M Stringer; John Carroll; David K Gardner; Maarten Van den Buuse; Natalie A Sims; William T Gibson; David L Adelson; Patrick S Western

doi:10.1186/s13148-022-01400-w

Transient Polycomb activity represses developmental genes in growing oocytes

Clin Epigenetics. 2022 Dec 21;14(1):183. doi: 10.1186/s13148-022-01400-w.

Authors

Ellen G Jarred^{1

2}, Zhipeng Qu³, Tesha Tsai^{1

2}, Ruby Oberin^{1

2}, Sigrid Petautschnig^{1

2}, Heidi Bildsoe^{1

2}, Stephen Pederson³, Qing-Hua Zhang⁴, Jessica M Stringer⁴, John Carroll⁴, David K Gardner⁵, Maarten Van den Buuse⁶, Natalie A Sims^{7

8}, William T Gibson⁹, David L Adelson^{3

10}, Patrick S Western^{11

12}

Affiliations

¹ Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia.
² Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
³ Department of Molecular and Biomedical Science, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
⁴ Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.
⁵ School of BioSciences, University of Melbourne, Parkville, VIC, Australia.
⁶ School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia.
⁷ Bone Cell Biology and Disease Unit, St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.
⁸ Department of Medicine at St, Vincent's Hospital, Fitzroy, VIC, Australia.
⁹ Department of Medical Genetics, University of British Columbia and British Columbia Children's Hospital Research Institute, Vancouver, BC, Canada.
¹⁰ South Australian Museum, SA, Adelaide, Australia.
¹¹ Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia. patrick.western@hudson.org.au.
¹² Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia. patrick.western@hudson.org.au.

Abstract

Background: Non-genetic disease inheritance and offspring phenotype are substantially influenced by germline epigenetic programming, including genomic imprinting. Loss of Polycomb Repressive Complex 2 (PRC2) function in oocytes causes non-genetically inherited effects on offspring, including embryonic growth restriction followed by post-natal offspring overgrowth. While PRC2-dependent non-canonical imprinting is likely to contribute, less is known about germline epigenetic programming of non-imprinted genes during oocyte growth. In addition, de novo germline mutations in genes encoding PRC2 lead to overgrowth syndromes in human patients, but the extent to which PRC2 activity is conserved in human oocytes is poorly understood.

Results: In this study, we identify a discrete period of early oocyte growth during which PRC2 is expressed in mouse growing oocytes. Deletion of Eed during this window led to the de-repression of 343 genes. A high proportion of these were developmental regulators, and the vast majority were not imprinted genes. Many of the de-repressed genes were also marked by the PRC2-dependent epigenetic modification histone 3 lysine 27 trimethylation (H3K27me3) in primary-secondary mouse oocytes, at a time concurrent with PRC2 expression. In addition, we found H3K27me3 was also enriched on many of these genes by the germinal vesicle (GV) stage in human oocytes, strongly indicating that this PRC2 function is conserved in the human germline. However, while the 343 genes were de-repressed in mouse oocytes lacking EED, they were not de-repressed in pre-implantation embryos and lost H3K27me3 during pre-implantation development. This implies that H3K27me3 is a transient feature that represses a wide range of genes in oocytes.

Conclusions: Together, these data indicate that EED has spatially and temporally distinct functions in the female germline to repress a wide range of developmentally important genes and that this activity is conserved in the mouse and human germlines.

Keywords: Epigenetic; H3K27me3; Inheritance; Oocyte; Polycomb; Programming.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA Methylation*
Genes, Developmental
Histones* / metabolism
Mice
Oocytes* / growth & development
Oocytes* / metabolism
Polycomb Repressive Complex 2* / genetics
Polycomb Repressive Complex 2* / metabolism

Substances

Histones
Polycomb Repressive Complex 2