Genomic imprinting in mouse blastocysts is predominantly associated with H3K27me3

Santini K*, Halbritter F*, Titz-Teixeira F, Suzuki T, Asami M, Ramesmayer J, Ma X, Lackner A, Warr N, Pauler F, Hippenmeyer S, Laue E, Farlik M, Bock C, Beyer A, Perry ACF & Leep M.


Nat Commun 12, 3804 (2021).

In mammalian genomes, differentially methylated regions (DMRs) and histone marks including trimethylation of histone 3 lysine 27 (H3K27me3) at imprinted genes are asymmetrically inherited to control parentally-biased gene expression. However, neither parent-of-origin-specific transcription nor imprints have been comprehensively mapped at the blastocyst stage of preimplantation development. Here, we address this by integrating transcriptomic and epigenomic approaches in mouse preimplantation embryos. We find that seventy-one genes exhibit previously unreported parent-of-origin-specific expression in blastocysts (nBiX: novel blastocyst-imprinted expressed). Uniparental expression of nBiX genes disappears soon after implantation. Micro-whole-genome bisulfite sequencing (µWGBS) of individual uniparental blastocysts detects 859 DMRs. We further find that 16% of nBiX genes are associated with a DMR, whereas most are associated with parentally-biased H3K27me3, suggesting a role for Polycomb-mediated imprinting in blastocysts. nBiX genes are clustered: five clusters contained at least one published imprinted gene, and five clusters exclusively contained nBiX genes. These data suggest that early development undergoes a complex program of stage-specific imprinting involving different tiers of regulation.

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Comparison of differential DNA methylation in uniparental blastocysts (y-axis) and parent-of-origin-specific gene expression (x-axis). Published and novel imprinted genes (nBiX and nBsX) are indicated in colour and other genes in grey. Each dot represents one gene associated with its closest DMR. Selected genes are labelled.

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Mice produced by mitotic reprogramming of sperm injected into haploid parthenogenotes

Toru Suzuki, Maki Asami, Martin Hoffmann, Xin Lu, Miodrag Guzˇvic´, Christoph A. Klein
& Anthony C.F. Perry

Nat Commun 7 (2016)

Sperm are highly differentiated and the activities that reprogram them for embryonic development during fertilization have historically been considered unique to the oocyte.

We here challenge this view and demonstrate that mouse embryos in the mitotic cell cycle can also directly reprogram sperm for full-term development. Developmentally incompetent haploid embryos (parthenogenotes) injected with sperm developed to produce healthy offspring at up to 24% of control rates, depending when in the embryonic cell cycle injection took place. This implies that most of the first embryonic cell cycle can be bypassed in sperm genome reprogramming for full development. Remodelling of histones and genomic 50-methylcytosine and 50-hydroxymethylcytosine following embryo injection were distinct from remodelling in fertilization and the resulting 2-cell embryos consistently possessed abnormal transcriptomes. These studies demonstrate plasticity in the reprogramming of terminally differentiated sperm nuclei and suggest that different epigenetic pathways or kinetics can establish totipotency.

A two cell embryo created using phICSI.

Fluorescence image (BrdU, maternal genome; PI, both genomes) show 2+1 class of nuclear configuration 14h after the first mitotic division (1C --> 2C) in phICSI-13 embryo.

White arrowhead: paternal chromatin.