Project description
Gene activation gone awry in embryos can have lifelong effects
Epigenetic changes are heritable changes in gene expression. They do not change the underlying DNA sequence coding in the gene but rather how a cell reads the gene. Given that these changes are inherited in daughter cells, epigenetic changes occurring immediately after fertilisation can have lifelong effects on an organism. DNA methylation, the addition of a methyl group (CH3), is an epigenetic change that usually leads to gene repression. One such instance during mouse embryogenesis leads to activation of the associated gene. When it does not occur, the gene is silent forever and the mice do not grow properly. DyNAmecs is investigating this unconventional effect of DNA methylation, epigenetic changes during this critical point of development, and their long-lasting effects.
Objective
Immediately after fertilization, mammalian genomes undergo a dramatic reshaping of the epigenome as the embryo transitions from the zygote into the pluripotent cells primed for lineage commitment. This is best exemplified by DNA methylation reprogramming, as the gametic patterns are largely erased, and the embryonic genome undergoes a wave of de novo DNA methylation. Moreover, once DNA methylation patterns are established, mechanisms faithfully maintain the mark across cell division. Thus, there is latent potential for DNA methylation deposited in the early embryo to exhibit a lifelong effect.
DNA methylation is a modification that is typically associated with gene repression at repetitive elements and at a minority of protein coding genes. I previously described the regulation of the Zdbf2 gene in mice, which is programmed during the de novo DNA methylation program. Challenging the paradigm, in this case DNA methylation is required for activation of a gene via antagonism of the polycomb-group of silencing proteins. If the DNA methylation fails to occur, the gene stays silent throughout life, resulting in a reduced growth phenotype.
For my proposed research I will utilize both a cell-based system that recapitulates these early embryonic events as well as an in vivo mouse model to investigate the extent and mechanisms of non-canonical DNA methylation functions. I plan to use a combinatorial approach of genomics, genetics, and proteomics in order to ascertain novel insights into DNA methylation-based regulation. Furthermore, I plan to employ precision epigenome editing tools to address the locus-specific impact of DNA methylation. Ultimately, I strive to gain a clear understanding of the profound epigenetic consequences of DNA methylation on this window of development, which occurs in the first week of mouse embryogenesis, and the second of human, but the repercussions of which can ripple throughout life.
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: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences developmental biology
- medical and health sciences clinical medicine embryology
- natural sciences biological sciences genetics genomes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
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ERC-STG - Starting Grant
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Call for proposal
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(opens in new window) ERC-2019-STG
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75794 PARIS
France
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