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Epigenetic Control of Mammalian Reproduction

Final Report Summary - EPIREPRO (Epigenetic Control of Mammalian Reproduction)

DNA methylation is an epigenetic mark that confers gene 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, using the mouse as a model. How are DNA methylation patterns shaped in the gametes (the spermatozoa and the egg)? How do they affect the production and identity of the gametes? Which part of this non-genetic information persists in the embryo, which part is erased? Does parental DNA methylation influence traits and phenotypes, and how? As a whole, this project was successful in providing novel and important insights in reproductive biology, by documenting new origins of infertilities and cases of non-genetic inheritance of traits and diseases.
In the first aim, we developed of a cellular system to study which control mechanisms are implemented upon DNA methylation withdrawal, a situation that naturally occurs during embryonic development. We used culture-induced DNA methylation loss in embryonic stem (ES) cells combined with innovative bioinformatic methods adapted to the analysis of transposon repeats. We found that after an initial phase of transcription burst, transposons are efficiently re-silenced through an epigenetic switch, where DNA methylation-based control is progressively replaced by repressive chromatin modifications. Using genome-wide loss-of-function screens, we further identified that conjointly to DNA methylation, m6A RNA modification represses transposons at the post-transcriptional level, by promoting the degradation of their transcripts. This work highlights that several mechanisms ensure 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 embryonic cells.
In the second aim, we relied on a forward genetic screen in the mouse to identify new transposon repressors acting in the male germline. Though this means, we discovered an unexpected novel member of the DNA methylation machinery, DNMT3C. 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. Transcriptional activity and active chromatin features define DNMT3C genomic targets, this suggesting that DNMT3C acts downstream of the piRNA cleavage pathway for the life-long protection of the heritable genetic material against transposons. Finally, we demonstrated the dichotomy of DNA methylation for spermatogenesis: DNMT3C deals with the 1% of the genome corresponding to young transposons with crucial implications for meiosis, while DNMT3A methylates the rest of the genome, and is required for germline stem cell homeostasis. Both enzymes are essential for male fertility.
The third aim was related to short- and long-term influences that parental DNA methylation may exert on phenotypes. We identified a locus -Socs5- that maintains life-long memory of the DNA methylation state inherited from the egg, yet this feature is not universal to all mouse strains and may underlie interindividual susceptibility to disease. We also found a maternally inherited DNA methylation mark that indelibly programs growth potential during the first days of embryonic development, by epigenetically marking Zdbf2, a gene we proved to be essential for the functioning of the pituitary-axis after birth, and hence, body size. Finally, we found that maternal DNA methylation inherited from the egg is essential for fine-tuning the awakening of the embryonic genome within the first hours after fertilization, with consequences on developmental rate and implantation success in the uterus.