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Endogenous retroviral insertions drive non-canonical imprinting in extra-embryonic tissues.

Published version
Peer-reviewed

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Authors

Pérez-Palacios, Raquel 
Gahurova, Lenka 
Schubert, Michael 
Krueger, Felix 

Abstract

BACKGROUND: Genomic imprinting is an epigenetic phenomenon that allows a subset of genes to be expressed mono-allelically based on the parent of origin and is typically regulated by differential DNA methylation inherited from gametes. Imprinting is pervasive in murine extra-embryonic lineages, and uniquely, the imprinting of several genes has been found to be conferred non-canonically through maternally inherited repressive histone modification H3K27me3. However, the underlying regulatory mechanisms of non-canonical imprinting in post-implantation development remain unexplored. RESULTS: We identify imprinted regions in post-implantation epiblast and extra-embryonic ectoderm (ExE) by assaying allelic histone modifications (H3K4me3, H3K36me3, H3K27me3), gene expression, and DNA methylation in reciprocal C57BL/6 and CAST hybrid embryos. We distinguish loci with DNA methylation-dependent (canonical) and independent (non-canonical) imprinting by assaying hybrid embryos with ablated maternally inherited DNA methylation. We find that non-canonical imprints are localized to endogenous retrovirus-K (ERVK) long terminal repeats (LTRs), which act as imprinted promoters specifically in extra-embryonic lineages. Transcribed ERVK LTRs are CpG-rich and located in close proximity to gene promoters, and imprinting status is determined by their epigenetic patterning in the oocyte. Finally, we show that oocyte-derived H3K27me3 associated with non-canonical imprints is not maintained beyond pre-implantation development at these elements and is replaced by secondary imprinted DNA methylation on the maternal allele in post-implantation ExE, while being completely silenced by bi-allelic DNA methylation in the epiblast. CONCLUSIONS: This study reveals distinct epigenetic mechanisms regulating non-canonical imprinted gene expression between embryonic and extra-embryonic development and identifies an integral role for ERVK LTR repetitive elements.

Description

Keywords

Development, Embryo, Endogenous retroviruses (ERVs), Extra-embryonic, Genomic imprinting, H3K27me3, Histone modifications, Long terminal repeats (LTRs), Non-canonical imprinting, Placenta, Animals, DNA Methylation, Female, Genomic Imprinting, Histone Code, Male, Maternal Inheritance, Mice, Retroviridae, Terminal Repeat Sequences

Journal Title

Genome Biol

Conference Name

Journal ISSN

1474-7596
1474-760X

Volume Title

20

Publisher

Springer Science and Business Media LLC