Recent evolution of a TET controlled and DPPA3/STELLA driven pathway of passive demethylation in mammals
International Joint Usage/Research Center Seminar
"Recent evolution of a TET controlled and DPPA3/STELLA driven pathway of passive demethylation in mammals"
Seminar Date and Time: 12/02/2019 (Monday) 14:00 ~ 15:00
Venue: Building 1, 1F, Big Auditorium
Speaker (Name): Heinrich Leonhardt
Affiliation, Title: Department of Biology, LMU Munich, Professor
Subject: Recent evolution of a TET controlled and DPPA3/STELLA driven pathway of passive demethylation in mammals
Genome-wide DNA demethylation is an essential and unique feature of mammalian development and defines naïve pluripotent cells in vivo and in vitro. So far, it was unclear how mammals specifically achieve and maintain global DNA hypomethylation during early development, given the high conservation of the DNA (de-)methylation machinery among vertebrates. Here, we describe a mammal-specific pathway in which active and passive DNA demethylation interact to achieve genome-wide demethylation in naïve pluripotent stem cells. In this pathway, TET proteins are necessary to maintain the demethylated state, but not - as previously thought - via genome-wide active demethylation. Rather, TET proteins actively demethylate promoters to regulate specific genes, including the naïve pluripotency and germline marker Dppa3 (Pgc7, Stella). DPPA3, in turn, drives genome-wide passive demethylation by directly binding and displacing UHRF1 from chromatin and thereby preventing the recruitment and activation of the maintenance DNA methyltransferase DNMT1. In contrast to other proteins known to be involved in active demethylation, DPPA3 is specific to mammals but is able to induce sweeping demethylation also in amphibians (Xenopus) and fish (medaka). Our results indicate that, while TET proteins initiate local and gene-specific demethylation in vertebrates, the evolutionary emergence of Dppa3 enabled genome-wide demethylation possibly facilitating epigenetic reprogramming during mammalian development.
Organizer (Host Researcher): Makoto Nakanishi