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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

Epigenetics Programme, Babraham Institute, Cambridge, UK.
Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.
Institut Curie, PSL University, Inserm, CNRS, Paris, France.
University of South Bohemia, Ceske Budejovice, Czech Republic.
Institute of Animal Physiology and Genetics, ASCR, Libechov, Czech Republic.
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Bioinformatics, Babraham Institute, Cambridge, UK.
Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg, Germany.
TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
Epigenetics Programme, Babraham Institute, Cambridge, UK.
Present Address: Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada.
Epigenetics Programme, Babraham Institute, Cambridge, UK.
Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.



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.


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.


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.


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

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