Germline DNA Demethylation Dynamics and Imprint Erasure through 5-hydroxymethylcytosine
By Jamie A. Hackett, Roopsha Sengupta, J. J. Żylicz, K. Murakami, Caroline Lee, Thomas A. Down, M. Surani. Science, 2012
749 citations recorded by the source corpus.
Epigenetic Controls Germ cells in mammals give rise to sperm and eggs. During their development, germ cells undergo extensive epigenetic reprogramming, including global DNA demethylation, which is vital for the totipotency of the developing embryo. Hackett et al. (p. 448) show that the enzymes Tet1 and Tet2 are involved in the demethylation of individual genes and in imprinted gametic differentially methylated regions. The enzymes were also responsible for the global conversion of CpG methylation to 5-hydroxymethylcytosine, which then progressively declines. The findings suggest that demethylation can occur by replication-coupled dilution, although active mechanisms cannot be excluded. A small number of loci escape demethylation, providing a possible mechanistic basis for transgenerational inheritance. Rare loci that escape epigenetic reprogramming in mammalian germ cells may underlie transgenerational epigenetic inheritance. Mouse primordial germ cells (PGCs) undergo sequential epigenetic changes and genome-wide DNA demethylation to reset the epigenome for totipotency. Here, we demonstrate that erasure of CpG methylation (5mC) in PGCs occurs via conversion to 5-hydroxymethylcytosine (5hmC), driven by high levels of TET1 and TET2. Global conversion to 5hmC initiates asynchronously among PGCs at embryonic day (E) 9.5 to E10.5 and accounts for the unique process of imprint erasure. Mechanistically, 5hmC enrichment is followed by its protracted decline thereafter at a rate consistent with replication-coupled dilution. The conversion to 5hmC is an important component of parallel redundant systems that drive comprehensive reprogramming in PGCs. Nonetheless, we identify rare regulatory elements that escape systematic DNA demethylation in PGCs, providing a potential mechanistic basis for transgenerational epigenetic inheritance.
Subfields: Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/132792af301d8222da15a89e8ee875a774fd6aec
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Genetics
In Molecular Biology
Citations in the corpus
- DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos (2014, background): “Active DNA demethylation in PGCs The two-phase demethylation process in PGCs (Guibert and Weber 2012; Seisenberger et al. 2012; Hackett et al. 2013; Yamaguchi et al. 2013) raises the question as to the molecular mechanisms involved in this distinction.”
- SOX17 is a Critical Specifier of Human Primordial Germ Cell Fate (2014, methodology): “We have established a foundation for future studies on resetting of the epigenome in hPGCLCs and hPGCs for totipotency and the transmission of genetic and epigenetic information.”
- A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development (2015, background): “Interestingly, as escapees are targeted for hydroxymethylation in mPGCs (Hackett et al., 2013), it is possible that these loci undergo a process of reiterative de novo methylation and hydroxymethylation.”
- Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, positive): “Expression of TET1/2 is upregulated in gonadal PGCs (relative to early PGCs and surround somatic cells) (Hackett et al., 2013; Yamaguchi et al., 2012), and antibody-based genomewide mapping of 5mC and 5hmC in PGCs indicates that 5mC is oxidized to 5hmC at many late demethylating loci between E9.”