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ERC

EPIREPRO Report Summary

Project ID: 616140
Funded under: FP7-IDEAS-ERC
Country: France

Mid-Term Report Summary - EPIREPRO (Epigenetic Control of Mammalian Reproduction)

DNA methylation is an autonomous epigenetic mark- with intrinsic stability and heritable properties- that provides a conserved form of transcriptional silencing and protection of genome integrity against transposons. The EpiREPRO grant set out to explore the role of DNA methylation in the control of mammalian reproduction. In particular, we are investigating how DNA methylation influences gametic production and identity and how it impacts on phenotypes in the short and long term.
The first aim of this project included the development of a cellular system to study the transition from DNA methylation-dependent to DNA methylation-independent control of the genome, as it occurs in embryonic and germline stem cells. For this, we used culture-induced DNA methylation loss in embryonic stem (ES) cells combined with innovative bioinformatic methods adapted to the analysis of transposon repeats in high throughput sequencing datasets. We found that after an initial phase of transcription burst, transposons of several classes are efficiently re-silenced through an epigenetic switch, where DNA methylation-based repression is progressively replaced by H3K27me3- or H3K9me3-mediated control. This work highlights that several adaptive chromatin responses to defective DNA methylation exist in embryonic stem cells: this ensures the control of a wide variety of transposon families in the long term and the maintenance of genome stability in developmental periods of intense DNA methylation changes.
In the second aim of the grant, we designed a forward genetic screen in the mouse to identify new transposon repressors acting the male germline. Though this means, we discovered a novel active member of the DNA methylation machinery, DNMT3C, which was previously annotated as a pseudogene. The most striking feature of DNMT3C is its extreme specificity: it only methylates the promoter of evolutionarily young transposons, only in the fetal male germline and has evolved specifically in rodent genomes by a duplication of Dnmt3B. The identification of a new mammalian DNA methyltransferase was totally unexpected; we are now trying to understand the molecular origin of DNMT3C target selectivity and the mechanism by which DNMT3C-less mammals – like men- control transposons during spermatogenesis. This should provide unprecedented insight into the role of DNA methylation in transposon silencing and fertility.
Finally, the third aim was related to the dissection of parental epigenetic influences on phenotypes, though genomic imprinting. Here, we found that a maternally inherited DNA methylation mark at the Zdbf2 locus indelibly programs growth potential during the first days of development after fertilization. We relied on both ES cells and mouse mutant models to reveal that this early epigenetic programming is not essential for the embryo itself but signals regulatory information to later stages of development, about the expression status of Zdbf2 in the post-natal brain and hence body size. This study provides one of the very few formal demonstrations of the existence of early epigenetic determination of adult phenotypes in mammals. As the Zdbf2 locus and its epigenetic regulation are conserved in mice and humans, we are now further investigating the dosage effect and molecular function of the Zdbf2 product on growth control.

Contact

Sylvie Le Coidic
Tel.: +33 1 56 24 65 14
Fax: +33 1 56 24 66 27
E-mail
Record Number: 196820 / Last updated on: 2017-04-12
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