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Medical Institute of Bioregulation Kyushu University
3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, JAPAN

The 804th MIB Seminar (Joint Usage/Research Center for the Multi-stratified Host Defense System)

This seminar is supported by the Ministry of Education, Science, Sports and Culture, Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area), Mechanisms underlying replication of non-genomic codes that mediate plasticity and robustness for cellular inheritance.

[Seminar in English]


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


Prof. Heinrich Leonhardt
Department of Biology, LMU Munich, Germany


Dec. 9 (Mon), 2019


Lecture Room 102, 1F, Biomedical Research Station, Hospital Campus
No.33 on the following linked map.


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.

Major Publications

  1. Karg E, Smets M, Ryan J, Forné I, Qin W, Mulholland CB, Kalideris G, Imhof A, Bultmann S and Leonhardt H.
    Ubiquitome analysis reveals PCNA-associated factor 15 (PAF15) as a specific ubiquitination target of UHRF1 in embryonic stem cells.
    J Mol Biol. 2017 Dec 8;429(24):3814-3824.
  2. Smets M, Link S, Wolf P, Schneider K, Solis V, Ryan J, Meilinger D, Qin W and Leonhardt H.
    DNMT1 mutations found in HSANIE patients affect interaction with UHRF1 and neuronal differentiation.
    Hum. Mol. Genet. 2017 Apr 15;26(8):1522-1534.
  3. Rottach A, Frauer C, Pichler G, Bonapace IM, Spada F and Leonhardt H.
    The multi-domain protein Np95 connects DNA methylation and histone modification.
    Nucl. Acids Res. 2010 Apr;38(6):1796-804.
  4. Meilinger D, Fellinger K, Bultmann S, Rothbauer U, Bonapace IM, Klinkert WE, Spada F and Leonhardt H.
    Np95 interacts with de novo DNA methyltransferases Dnmt3a and 3b, and mediates epigenetic silencing of the viral CMV promoter in embryonic stem cells.
    EMBO Rep. 2009 Nov;10(11):1259-64.


Division of Epigenomics and Development, Medical Institute of Bioregulation
Motoko UNOKI
TEL: 092 (642) 6761

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