Epigenetic Regulation of normal hematopoiesis and its dysregulation in myeloid neoplasia

Functional analysis of histone demethylases in the regulation of bivalent chromatin states during hematopoietic development and in adult HSCs

The multiple cell lineages of the hematopoietic system are continuously regenerated by hematopoietic stem cells (HSCs). While a stable pool of HSCs is maintained by self-renewal, the multipotent HSCs continuously differentiate to produce a large number of myelo/erythroid and lymphoid effector cell types. Recent progress in HSC research revealed intrinsic as well as extrinsic factors and epigenetic mechanisms that are involved in the self-renewal and differentiation of HSCs.
Seminal studies have demonstrated the relevance of histone methylation for the development, maintenance and differentiation of HSCs. Specific histone methylation patterns, so called bivalent chromatin domains, have been linked to the regulation of hematopoietic expression programs. Bivalent domains are established by the concerted action of polycomb and trithorax complexes and are characterized by the simultaneous presence of activating and repressive histone methylation marks. They are associated with transcriptionally poised states of hematopoietic genes. Bivalent chromatin marks are lost during hematopoietic differentiation. The relevance of histone demethylases for HSC biology has so far not been addressed.

Thus our hypothesis is that a molecular understanding of how histone demethylases contribute to the establishment and maintenance of hematopoietic expression programs will improve our understanding of how histone methylation contributes to HSC development, self-renewal and differentiation.
We therefore propose to study the function of histone demethylases via reversible shRNA-targeted knockdown in the early hematopoietic progenitor compartment in an embryonic stem cell (ESC) differentiation system and in HSCs of shRNA transgenic mice. We expect this analysis to provide important new insight into the regulatory circuitry of histone methylation that is key to HSC development and function.

  • Benedikt A, Baltruschat S, Scholz B, Bursen A, Arrey TN, Meyer B, Varagnolo L, Müller AM, Karas M, Dingermann T, Marschalek R. (2011) The leukemogenic AF4-MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures. Leukemia, 25: 135-144. PMID:21030982

  • Walenda T, Bokermann G, Ferreria MV, Piroth D, Hieronymus T, Neuss-Stein S, Zenke M, Ho AD, Müller AM and Wagner W. (2011) Synergistic effects of growth factors and mesenchymal stromal cells for expansion of hematopoietic stem and progenitor cells. Exp. Hematol, 39: 617-628. PMID: 21356269

  • Sienerth AR, Scheuermann C, Galmiche A, Rapp UR, Becker M. (2011) Polycomb group protein Bmi1 negatively regulates IL-10 expression in activated macrophages. Immunol Cell Biol, 89: 812–816. PMID:21221124

  • Albrecht Müller

    University of Würzburg
    Zinklesweg 10
    D-97078 Würzburg, Germany
    Phone +49-931-20145848
    Assistant +49-931-201-45478/45146
    Fax +49-931-20145147

    Matthias Becker

    University of Würzburg
    Zinklesweg 10
    D-97078 Würzburg, Germany
    Phone +49-931-20145851
    Fax +49-931-20145147




    Christine Hofstetter
    Justyna Kampka