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Abstract
Genome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. Here, we describe a recently evolved pathway in which global hypomethylation is achieved by the coupling of active and passive demethylation. TET activity is required, albeit indirectly, for global demethylation, which mostly occurs at sites devoid of TET binding. Instead, TET-mediated active demethylation is locus-specific and necessary for activating a subset of genes, including the naïve pluripotency and germline marker Dppa3 (Stella, Pgc7). DPPA3 in turn drives large-scale passive demethylation by directly binding and displacing UHRF1 from chromatin, thereby inhibiting maintenance DNA methylation. Although unique to mammals, we show that DPPA3 alone is capable of inducing global DNA demethylation in non-mammalian species (Xenopus and medaka) despite their evolutionary divergence from mammals more than 300 million years ago. Our findings suggest that the evolution of Dppa3 facilitated the emergence of global DNA demethylation in mammals.
Highlights
During early embryonic development the epigenome undergoes massive changes
By dissecting the contribution of the catalytic activity of TET1 and TET2 to global hypomethylation, we find that Ten-eleven translocation (TET)-mediated active demethylation drives the expression of the Developmental pluripotencyassociated protein 3 (DPPA3/PGC7/STELLA)
This widespread DNA hypermethylation was reminiscent of the global increase in DNA methylation accompanying the transition of naïve embryonic stem cells (ESCs) to primed epiblast-like cells (EpiLCs)[54,56,57], which prompted us to investigate whether the DNA methylation signature in T1CM, T2CM, and T12CM ESCs resembles that of more differentiated cells
Summary
During early embryonic development the epigenome undergoes massive changes. Upon fertilization, the genomes of highly specialized cell types—sperm and oocyte— need to be reprogrammed in order to obtain totipotency. DNA methylation can be reversed to unmodified cytosine by two mechanisms; either actively by Ten-eleven translocation (TET) dioxygenase-mediated oxidation of 5mC in concert with the base excision repair machinery[22,23,24,25] or passively by a lack of functional DNA methylation maintenance during the DNA replication cycle[26,27] Both active and passive demethylation pathways have been implicated in the genome-wide erasure of 5mC accompanying mammalian preimplantation development[28,29,30,31,32,33,34]. Our study uncovers a novel TET-controlled and DPPA3-driven pathway for passive demethylation in naïve pluripotency in mammals
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