Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals

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.

Navigating the DNA methylation landscape of cancer

“…Early studies showed that PGC7 protects DNA methylation pattern during early embryogenesis via inhibition of TET2/TET3 [80,81]. Recently, however, it has been reported that PGC7, on the contrary, functions as a negative regulator of UHRF1/DNMT1-dependent DNA methylation by interacting with the PHD domain of UHRF1 [82][83][84]. Analysis of tissue microarray comprising 107 pairs of HCC tissues from human patients and their non-tumor counterparts revealed that PGC7 expression was significantly upregulated in advanced stage tumors and PGC7 positive cells were associated with poor clinical outcome.…”

Get Out and Stay Out: New Insights Into DNA Methylation Reprogramming in Mammals

“…It was demonstrated that the underlying reason for such low methylation was impaired UHRF1 activity (von Meyenn et al, 2016 ). While initially UHRF1 was shown to be unstable at the post-translational level in 2i ESCs (von Meyenn et al, 2016 ), subsequently it was demonstrated that DPPA3 is the factor that is impeding UHRF1 function (Mulholland et al, 2020 ). Through a rigorous set of biochemical and microscopy-based experiments, Mulholland et al showed that DPPA3 binds to UHRF1, thus impairing the latter's ability to bind to chromatin ( Figure 1 ).…”

“…Finally, Mulholland et al showed that TET1 and TET2 are required for demethylation of Dppa3 regulatory regions, thus its activation ( Figure 1 ) (Mulholland et al, 2020 ). In other words, targeted demethylation of one gene supports global passive demethylation.…”

“…Amazingly, when the mouse DPPA3 protein was incubated with the egg extracts of the amphibian Xenopus laevis , the mouse protein inhibited the frog UHRF1. Furthermore, when the fertilized eggs from the model fish medaka were injected with Dppa3 mRNA, the embryos exhibited dramatic hypomethylation (Mulholland et al, 2020 ). Therefore, DPPA3 has evolved as a potent DNA demethylation factor that can disrupt UHRF1 function in distant species.…”

Epiblast morphogenesis is controlled by selective mRNA decay triggered by LIN28A relocation

“…Remaining masks were then used to measure intensity of Lin28A inside the nucleus. To measure intensity in the cytoplasm, we enlarged the masks by 3 pixels, and took the intensity along the perimeter of the enlarged mask as a readout for intensity in the cytoplasm (discarding pixels which lay in neighbouring masks), similarly to cytoplasm intensity measurements carried out elsewhere (Mulholland et al, 2020) .…”