DS04 - Vie, santé et bien-être

DNMT3C, a new DNA methylation player in transposon control and mammalian fertility – SPERMethyl

Submission summary

DNA methylation is prevalent in mammalian genomes and plays a central role in the epigenetic control of development. Accordingly, abnormal methylation patterns are associated with embryonic lethality, neuro-developmental syndromes, immunodeficiency, infertility and cancer. Therefore, it is fundamental to understand the rules that govern the spatio-temporal specificity of DNA methylation patterns and their impact on health and diseases.
Transposon silencing has been proposed to be the driving force for the evolution of DNA methylation in mammals. Millions of transposable elements reside in mammalian genomes, far surpassing in number the approximately 25,000 protein-coding genes. Through their activity or their mere presence, transposons can bring beneficial innovations for the evolution of the host genome but they can also be deleterious for its integrity: they can disrupt gene functions through insertional mutagenesis, influence gene transcription by position effects or induce chromosomal rearrangements through non-allelic recombination. DNA methylation-driven repression of transposons is particularly crucial for the protection of the germline and the hereditary material and therefore, for the fitness of the species.
The mammalian DNA methylation machinery was thought to be composed of three catalytically active DNA methyltransferases and one accessory protein. Establishment of DNA methylation patterns relies on the de novo enzymes, DNMT3A and DNMT3B, with the assistance of the DNMT3L co-factor. Once established, DNA methylation patterns are propagated throughout cell divisions by the maintenance DNMT1 enzyme. Thorough inspection of the mammalian genome sequences had led to the conclusion that all the functional members of this family were known and that all DNA methylation-related processes should be explained by this set of protagonists.
However, we recently uncovered a new DNA methyltransferase, DNMT3C. The most striking characteristics of DNMT3C is its high level of specialization: it selectively methylates the promoters of evolutionary young retrotransposons and only in the context of fetal spermatogenesis. Moreover, it specifically evolved in rodents, by tandem duplication of the Dnmt3B gene. Strikingly, its function is absolutely non-redundant with DNMT3B; transposons get massively reactivated in germ cells of male Dnmt3C mutant mice, in association with a complete sterility phenotype. Such strict requirement of DNMT3C for fertility in rodents raises the question as to how DNMT3C-less mammals, men included, protect their gametes against transposons.
Our discovery of DNMT3C raises a new set of challenges to the current views of the evolution of DNA methyltransferases, the regulation of the de novo methylation process and its tight links with the selective pressure to epigenetically control transposons in the germ line and to protect reproductive functions, in mice and men. The SPERMethyl program aims at characterizing this unexpected new DNA methylation player: what is the position of DNMT3C within the DNA methylation system and its role relative with the other DNMTs during spermatogenesis? Which protein partners and chromatin states define the exquisite specificity of DNMT3C towards transposons? What is relationship between DNMT3C and its paralog DNMT3B? Do they perform the same function in mice and men, respectively, and are they interchangeable? To achieve our objectives, we have assembled the full collection of Dnmt3 mutant mice and we will combine in vivo genetic editing, developmental analyses, biochemical assays and genome-scale profiling of DNA methylation, transcription and chromatin states. As a whole, our program will unravel the essential principles of the epigenetic regulation of transposons in the germline and their importance for safe guarding reproductive fitness.

Project coordination

Deborah BOURC'HIS (INSTITUT CURIE - SECT DE RECHERCHE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IC INSTITUT CURIE - SECT DE RECHERCHE
BSC Biotechnologie et signalisation cellulaire

Help of the ANR 395,688 euros
Beginning and duration of the scientific project: - 36 Months

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