Project description
Deciphering the functions of global hypomethylation in the germline
In the developing germline of mammals DNA methylation, an epigenetic mark that is normally crucial for maintaining genome stability, is erased. This hypomethylated state is transient in males but is maintained in female germ cells, or oocytes, until puberty. The ERC-funded hypomethGENOME project will study the consequences of this hypomethylation in germ cells and oocytes. To do this, the team will use transgenic mouse models and pioneer a method to study epigenome propagation in vivo. By tracking DNA molecules and their methyl marks across division in living mammals and embryos, hypomethGENOME will uncover the functions and implications of global hypomethylation in the germline.
Objective
Replication in S phase duplicates not only the genome but also the epigenome, to ensure cell identity is propagated and genome stability maintained in daughter cells. Epigenome propagation in development has been understudied due to lack of appropriate methods, even though replication is widely accepted to be a primary vehicle through which programmed epigenetic changes occur in vivo. In mammalian germline development, the epigenome is reprogrammed via impairment of the epigenome maintenance network. By dividing without maintaining core components of the epigenome, primordial germ cells harbor genomes devoid of the crucial repressive mark DNA methylation. Hypomethylation is destabilizing because it de-represses transposable elements. Despite this, oocytes arrest in a hypomethylated state, regaining methylation only in preparation for ovulation as part of puberty. In parallel, two-thirds of the oocyte pool dies around birth in mammals, and the features delineating oocytes that survive this process from those that die are unclear.
I propose that hypomethylation is alternately selected for and against across gametogenesis. Specifically, that hypomethylation a positive feature in primordial germ cells but a deleterious feature in the female germline after sex specification. To test this, we will develop novel transgenic mouse models and technologies to study epigenome propagation in vivo, and utilize state-of-the-art sequencing, mass spectrometry, microscopy, and metabolic labelling approaches. By developing a method for tracking DNA molecules and their associated methyl marks across division in live animals and embryos, we will establish an unprecedented technology for understanding epigenome propagation in development. Cumulatively, this work will uncover the functions and consequences of global hypomethylation in the germline, and provide groundbreaking insights into the nature of mitotic and intergenerational epigenetic inheritance in vivo.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciencesbiological sciencesgeneticsDNA
- natural sciencesphysical sciencesopticsmicroscopy
- natural sciencesbiological scienceszoologymammalogy
- medical and health sciencesclinical medicineembryology
- natural sciencesbiological sciencesgeneticsgenomes
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Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
1165 Kobenhavn
Denmark