Epigenetic Engineering

    Principle investigator Dr. Stefan H. Stricker joined the Institute for Stem Cell Research at the Helmholtz Zentrum München as a guest scientist associated with the Ludwig-Maximilians-Universität Munich. Since December 2016 he is the head of the MCN Junior Research group "Epigenome Editing" at the BioMedical Center.

    Specific questions:

    The research aim of the lab is to investigate, which of the myriad of epigenetic marks have significant functional relevance in mediating stem cell or disease phenotypes.

    • Which epigenetic marks trigger these phenotypes?
    • Where are they located and how do they work?
    • How are they deposited by other epigenetic mechanisms?

    Our tools and models:

    To address these questions we develop, modify and use the following tools and models:

    Nuclear Reprogramming of brain cancer cells:

    We have demonstrated that lineage reprogramming to pluripotency through forced expression of reprogramming transcription factors (termed induced pluripotent stem cell [iPSC] technology) can be applied to study epigenetic mechanisms in human cancer (Stricker et al., 2013; Stricker and Pollard, 2014). Such experimentally induced reprogramming provides a cellular model to assess the functional contribution of both cancer-specific and lineage-associated epigenetic changes in maintaining the malignant cellular state.

    Stricker et al., Genes and Development2013

    Stricker et al., Genes and Development, 2013

    G-iPSCs gained expression of pluripotency associated genes and extinguished neural lineage marker gene expression. This process led to the resetting of a large proportion of developmentally defined and cancer-associated DNA methylation marks. G-iPSCs remained capable of commitment to neural lineages allowing us to explore the consequences of the epigenomic resetting of cancer specific modifications in the context of appropriate developmental lineage – something that has not reported in recent iPSC studies of human cancers. We found that the widespread resetting of DNA methylation alone had no detectable effect on the tumourigenicity of these cells. Thus, widespread resetting of cancer-associated DNA methylation is not sufficient to suppress malignant cellular behaviour.

     Stricker et al., Genes and Development, 2013

    To explore whether a cancer genome strictly operates in one specific developmental lineage we also directed GiPSCs in vitro along the mesodermal lineage – generating proliferative cartilage progenitors that were then transplanted in vivo. We found that these cells lost the ability to form malignant brain tumours. Reconfiguration of the network of ‘cell fate’ transcription factors and consequently the downstream developmental epigenetic mechanisms effectively silenced cancer-promoting pathways that are essential for the cells to display uncontrolled proliferation and infiltration.

    Stricker et al., Epigenetics, 2014