Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline
| Autor: | Ian R. Adams, M. Azim Surani, Judith Reichmann, Richard R. Meehan, James P. Reddington, Colm E. Nestor, Wolf Reik, Donncha S. Dunican, Jamie A. Hackett, Miguel R. Branco |
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| Rok vydání: | 2012 |
| Předmět: |
Embryonic Development
Biology Epigenesis Genetic Mice Epigenetics of physical exercise Histone methylation Animals Cancer epigenetics Epigenetics Promoter Regions Genetic Molecular Biology RNA-Directed DNA Methylation Cells Cultured Research Articles Epigenomics Genetics Genome DNA Methylation Chromatin Assembly and Disassembly Embryo Mammalian Mice Inbred C57BL Germ Cells Cytoprotection DNA methylation NIH 3T3 Cells Reprogramming DNA Damage Developmental Biology |
| Zdroj: | Development. 139:3623-3632 |
| ISSN: | 1477-9129 0950-1991 |
| Popis: | Mouse primordial germ cells (PGCs) erase global DNA methylation (5mC) as part of the comprehensive epigenetic reprogramming that occurs during PGC development. 5mC plays an important role in maintaining stable gene silencing and repression of transposable elements (TE) but it is not clear how the extensive loss of DNA methylation impacts on gene expression and TE repression in developing PGCs. Using a novel epigenetic disruption and recovery screen and genetic analyses, we identified a core set of germline-specific genes that are dependent exclusively on promoter DNA methylation for initiation and maintenance of developmental silencing. These gene promoters appear to possess a specialised chromatin environment that does not acquire any of the repressive H3K27me3, H3K9me2, H3K9me3 or H4K20me3 histone modifications when silenced by DNA methylation. Intriguingly, this methylation-dependent subset is highly enriched in genes with roles in suppressing TE activity in germ cells. We show that the mechanism for developmental regulation of the germline genome-defence genes involves DNMT3B-dependent de novo DNA methylation. These genes are then activated by lineage-specific promoter demethylation during distinct global epigenetic reprogramming events in migratory (∼E8.5) and post-migratory (E10.5-11.5) PGCs. We propose that genes involved in genome defence are developmentally regulated primarily by promoter DNA methylation as a sensory mechanism that is coupled to the potential for TE activation during global 5mC erasure, thereby acting as a failsafe to ensure TE suppression and maintain genomic integrity in the germline. |
| Databáze: | OpenAIRE |
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