Epigenetic Regulation of normal hematopoiesis and its dysregulation in myeloid neoplasia

Regulation of RUNX1 activity by the protein arginine methyltransferase 6

The transcription factor RUNX1 is crucial for the development of definitive hematopoietic stem cells (HSC). RUNX1 activity is altered in human leukaemia by mutation, deletion and chromosomal translocation. The recruitment of chromatin modifying co-factors by RUNX1 can lead to epigenetic changes of gene expression.
We could show that RUNX1 interacts with the protein arginine methyltransferase 6 (PRMT6).
Our preliminary results demonstrate that PRMT6 can methylate RUNX1 and influences its gene regulatory activity. PRMT6 is also able to methylate histone tails and contributes to the histone code that is determining the epigenetic state of the given locus. Hence recruitment of PRMT6 to RUNX1 target genes leads to arginine methylation of histone tails.

In this project the molecular influence of PRMT6 on RUNX1 and the epigenetic consequences of PRMT6 recruitment to target genes by RUNX1 are examined. These investigations may uncover molecular targets for a therapeutic intervention of RUNX1 dependent leukaemia.

  • Herglotz J., Kuvardina O.N., Kolodziej, S., Kumar, A., Hussong, H., Grez, M., Lausen, J.(2012). Histone arginine methylation keeps RUNX1 target genes in an intermediate state. Oncogene. Jul 9. doi: 10.1038/onc.2012.274. PMID:22777353

  • Wichmann C., Grez M., Lausen J. (2010) Molecular Targeting of Aberrant Transcription Factors in Leukemia: Strategies for RUNX1/ETO. Current Drug Targets, 11(9): 1181 – 91. PMID:20583973

  • Wichmann C., Becker Y., Chen-Wichmann L., Vogel V., Vojtkova A., Herglotz J., Moore S., Koch J., Lausen J., Mäntele W., Gohlke H., Grez M. (2010) Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity. Blood, 116(4): 603 – 13. PMID:20430957

  • Lausen J., Pless O., Leonard F., Kuvardina O.N., Koch B., Leutz A. (2010) Targets of the Tal1 transcription factor in erythrocytes: E2 ubiquitin conjugase regulation by Tal1. J Biol Chem, 285(8): 5338 – 46. PMID:20028976

  • Pless O., Kowenz-Leutz E., Knoblich M., Lausen J.; Beyermann M.; Walsh M.J.; Leutz A. (2008) G9a-mediated lysine methylation alters the function of CCAAT/enhancer-binding protein-beta. J. Biol. Chem. 283(39): 26357-63. PMID:18647749

  • Wei Y., Liu S., Lausen J., Cho S., Biris N., Kobayashi N., Wei Y., Yokoyama S., Werner M.H. (2007) A TAF4-homology domain from the co-repressor Eight Twenty-one (ETO) is a docking platform for positive and negative regulators of transcription. Nat. Struct. Mol. Biol. 14(7): 653-661. PMID:17572682

  • Lausen J., Liu S., Fliegauf M., Lubbert M., Werner M.H. (2006) ELA2 is regulated by hematopoietic transcription factors, but not repressed by AML1-ETO. Oncogene 25(9): 1349-57. PMID:16247445

  • Lausen, J.; Cho, S.; Liu, S.; Werner, M.H.: The nuclear receptor co-repressor (N-CoR) utilizes repression domains I and III for interaction and co-repression with ETO. J. Biol. Chem. 279(47): 49281-8. 2004. PMID:15377655

  • Jörn Lausen

    Georg-Speyer-Haus Institute for Biomedical Research
    Paul-Ehrlich-Str 42-44
    D-60596 Frankfurt, Germany
    Phone +49-69-63395187
    Fax +49-69-63395-231




    Nicole Kohrs
    Stefanie Herkt
    Olga Lausen