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Genome Biol. 2019 Oct 29;20(1):225. doi: 10.1186/s13059-019-1833-x.

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

Author information

1
Epigenetics Programme, Babraham Institute, Cambridge, UK. courtney.hanna@babraham.ac.uk.
2
Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. courtney.hanna@babraham.ac.uk.
3
Institut Curie, PSL University, Inserm, CNRS, Paris, France.
4
University of South Bohemia, Ceske Budejovice, Czech Republic.
5
Institute of Animal Physiology and Genetics, ASCR, Libechov, Czech Republic.
6
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
7
Bioinformatics, Babraham Institute, Cambridge, UK.
8
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany.
9
TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
10
Epigenetics Programme, Babraham Institute, Cambridge, UK.
11
Present Address: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada.
12
Epigenetics Programme, Babraham Institute, Cambridge, UK. gavin.kelsey@babraham.ac.uk.
13
Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. gavin.kelsey@babraham.ac.uk.

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.

KEYWORDS:

Development; Embryo; Endogenous retroviruses (ERVs); Extra-embryonic; Genomic imprinting; H3K27me3; Histone modifications; Long terminal repeats (LTRs); Non-canonical imprinting; Placenta

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