Epigenetic Regulation of normal hematopoiesis and its dysregulation in myeloid neoplasia

Development of bioinformatic methods for investigation of epigenetic mechanisms in MDS and AML and prediction of therapy falilure in treatment of MDS with valproic acid


In this subproject, we are developing bioinformatic methods to process data on epigenetic marks from other subprojects, and to reveal the corresponding mechanisms of gene regulation. Such marks comprise chemical modifications of histone proteins, the methylation of cytosine residues in DNA, and the expression of non-coding RNAs. Changes in the presence or quantitative levels of such epigenetic marks follow certain patterns along hematopoietic differentiation, and are changed in malignant dieseases like myelodysplastic syndrome (MDS) or myeloid leukemias in a characteristic manner.
The genome-wide detection of epigenetic marks is done by methods like chromatin immunoprecipitation using suitable antibodies and subsequent sequencing of enriched DNA fragments. DNA methylation can also be investigated by enrichment techniques (MeDIP, MCIP), or by sequencing of total DNA that has been chemically converted by bisulfite. Bioinformatic analysis consists of mapping of sequenced fragments to a reference genome, detection of significantly enriched genomic regions (peak detection), and comparative analysis by statistical algorithms between biologically defined states. We develop here standardized pipelines that can be used from other partners of this DFG priority program.
In addition, we want to associated observed changes in epigenetic marks with clinical parameters like course of disease and therapy response in treatment with drugs that show epigenetic effects (e.g., valproic acid). From changes in epigenetic marks, we also aim to build gene regulatory models that allow to understand pathogenetic mechanisms in malignant myeloid diseases as influenced by epigenetics.


  • Bruns I, Czibere A, Fischer JC, Roels F, Cadeddu R-P, Buest S, Bruennert D, Huenerlituerkoglu AN, Stoecklein NH, Singh R, Zerbini LF, Jäger M, Kobbe G, Gattermann N, Kronenwett R, Brors B, Haas R. (2009) The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence. Leukemia, 23:892–899. PMID:19158832

  • International Cancer Genome Consortium, Hudson TJ, Anderson W, Artez A, Barker AD, Bell C, Bernabé RR, Bhan MK, Calvo F, Eerola I, Gerhard DS, Guttmacher A, Guyer M, Hemsley FM, Jennings JL, Kerr D, Klatt P, Kolar P, Kusada J, Lane DP, Laplace F, Youyong L, Nettekoven G, Ozenberger B, Peterson J, Rao TS, Remacle J, Schafer AJ, Shibata T, Stratton MR, et al.(2010) International network of cancer genome projects. Nature, 464:993–998. PMID:20393554


  • Benedikt Brors


    German Cancer Research Center (DKFZ)
    Im Neuenheimer Feld 280
    D-69120 Heidelberg, Germany
    Phone +49-6221-423614
    Fax +49-6221-423620
    b.brors@dkfz-heidelberg.de


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    Prakash G. Balasubramanian