H3K9 Methyltransferase EHMT2/G9a Controls ERVK-Driven Noncanonical Imprinted Genes

Abstract

Aim: Paternal allele-specific expression of noncanonical imprinted genes in the extraembryonic lineages depends on an H3K27me3-based imprint in the oocyte, which is not a lasting mark. We hypothesized that EHMT2, the main euchromatic H3K9 dimethyltransferase, also has a role in controlling noncanonical imprinting. Methods: We carried out allele-specific total RNA-seq analysis in the ectoplacental cone of somite-matched 8.5 dayspost coitum embryos using reciprocal mouse crosses. Results: We found that the maternal allele of noncanonical imprinted genes was derepressed from its ERVK promoter in the Ehmt2^-/- ectoplacental cone. In Ehmt2^-/- embryos, loss of DNA methylation accompanied biallelic derepression of the ERVK promoters. Canonical imprinting and imprinted X chromosome inactivation were generally undisturbed. Conclusion: EHMT2 is essential for repressing the maternal allele in noncanonical imprinting.

Keywords: :

• EHMT2
• ERVK promoters
• G9a
• noncanonical imprinted genes
• placenta

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2021-0204

Author contributions

Conceptualization and study design: PE Szabó. Data acquisition: T-B Zeng, J Liao and PE Szabó. Analysis: N Pierce, T-B Zeng and PE Szabó. Interpretation: T-B Zeng and PE Szabó. Drafting the manuscript: T-B Zeng and PE Szabó. Revising and final approval of the manuscript: T-B Zeng, N Pierce, J Liao and PE Szabó. Accountability: T-B Zeng, N Pierce, J Liao and PE Szabó.

Acknowledgments

The authors are grateful to G Kelsey and C Hanna for sharing their H3K4me3 allele-specific ChIP-seq data. They also thank G Pfeifer for helpful discussions, D Chandler for their comments on the manuscript, the VAI Genomics Core for RNA deep sequencing and the VAI Vivarium for mouse maintenance and husbandry.

Financial & competing interests disclosure

This work was funded by VAI. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations.

Data availability

The RNA-seq datasets generated in this study have been deposited in the Gene Expression Omnibus under accession number GSE160455 and GSE156538. Allele-specific H3K4me3 ChIP-seq data in E6.5 ExE are based on GEO submission GSE124216. WGBS data of sperm and oocyte were obtained from GSE56697.

Additional information

Funding

This work was funded by VAI. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.