Research Becker Group

Projects

Function of chromatin modifying factors in age-associated diseases like osteoporosis and cancer (joint project with Franz Jakob)

Age-associated modifications of chromatin structure and the resulting changes in gene regulation patterns are underlying causes of aging and age-related diseases like osteoporosis, atherosclerosis and tumor development. Chromatin regulators such as Polycomb group Protein BMI1 and Lymphocyte-specific helicase (LSH/HELLS/SMARCA6/PASG) are key regulators of chromatin structure. Studies using transgenic and gene ablation strategies revealed that both are tightly involved in bone homeostasis and senescence induction, rendering them attractive targets for the treatment of age-related diseases. BMI1 and LSH are important regulators of fail-safe programs such as replicative senescence, which lower the risk of tumor development. Moreover they are also regulators of osteogenic differentiation and bone formation in vitro and in vivo. This project addresses the question if chromatin modulators like BMI1 and LSH can be targeted for regenerative therapy of aging tissues without impairing important cell cylcle control mechanisms for the avoidance of tumor development.

Functional analysis of KDM6A histone demethylase in the regulation of HSC development and in leukemogenesis (joint project with Albrecht Müller)

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, multipotent HSCs continuously differentiate to produce a large number of myelo/erythroid and lymphoid cell types. For the execution of coordinated self-renewal and differentiation the establishment and maintenance of specific gene expression programs is required. Lineage-specific histone methylation patterns are linked to the regulation of hematopoietic expression programs. The underlying histone methyl transferase activities are mediated by multiprotein complexes with opposing functions that belong to the polycomb- and trithorax group, respectively. Recently a histone H3K27me3-specific histone demethylase (KDM6A, alias UTX) has been identified as part of the trithorax complexes MLL2/3. In the corse of this project we analyze the genome-wide binding of KMD6A during ES cell hematopoiesis and the genomic network of KDM6A during leukemogenesis.

Supported by

IZKF - Interdisziplinären Zentrum für Klinische Forschung der Universität Würzburg

Collaborators

Prof. Dr. Karen Bieback, University Hospital Heidelberg
Prof. Dr. Torsten Blunk, University Würzburg
Prof. Dr. Hartmut Geiger, University Ulm
Prof. Dr. Ulrich Hofmann, University Würzburg

Publications

Becker, M., Potapenko, T., Niklaus, A., Bieback, K., Ho, A., Müller, A.M. (2016) Polycomb Protein BMI1 Regulates Osteogenic Differentiation of Human Adipose Tissue-Derived Mesenchymal Stem Cells Downstream of GSK3. Stem Cells Dev. 25(12):922-33. doi: 10.1089/scd.2015.0277

Hofstetter, C., Kampka, J., Huppertz, S.,Weber, H., Schlosser, A., Müller, A.M., Becker, M. (2016) Inhibition of KDM6 activity during murine ES cell differentiation induces DNA damage. J Cell Sci: doi: 10.1242 /jcs. 175174

Zdzieblo, D., Li, X., Lin, Q., Zenke, M., Illich, D.J., Becker, M. and Müller, A.M. (2014) Pcgf6, a polycomb group protein, regulates mesodermal lineage differentiation in murine ES cells and functions in iPS reprogramming. Stem Cells 32(12):3112-25. doi: 10.1002/stem.1826

Bieback, K., Hecker, A., Schlechter, T., Hofmann, I., Brousos, N., Redmer, T., Besser, D., Klüter, H., Müller, A.M., and Becker, M. (2012) Replicative aging and differentiation potential of human adipose tissue-derived mesenchymal stromal cells expanded in pooled human or fetal bovine serum. Cytotherapy 14(5):570-83

Sienerth, A.R., Scheuermann, C., Galmiche, A., Rapp, U.R., and Becker, M. (2011) Polycomb group protein Bmi1 negatively regulates IL-10 expression in activated macrophages. Immunol. Cell Biol. 89(7):812-6

Becker, M., Korn, C., Sienerth A.R., Voswinckel, R., Luetkenhaus K., and Rapp U.R. (2009) Polycomb group protein Bmi-1 is required for growth of RAF driven non-small-cell lung cancer. PLoS One 4(1): e4230

Qiu, Y., Zhao, Y., Becker, M., John, S., Parekh, B.S., Huang, S., Hendrawanto, A., Martinez, E.D., Chen, Y., Lu, H., Adkins , N. L., Stavreva, D.A.,Wiench, M., Georgel, P.T., Schiltz R.L. and Hager, G.L. (2006) HDAC1 acetylation is linked to progressive modulation of steroid receptor induced gene transcription Mol. Cell 22(5): 669-79

Becker, M., Becker, A., Miyara, F., Han, Z., Kihara, M., Brown, D.T., Hager, G.L., Latham, K., Adashi, E.Y., and Misteli, T. (2005) Differential in vivo binding dynamics of somatic and oocyte-specific linker histones in oocytes and during ES cell nuclear transfer Mol. Biol. Cell 16: 3887-3895

Becker, M., Baumann C., John, S., Walker, D. A., Vigneron, M., McNally, J., and Hager G.L. (2002) Dynamic behavior of transcription factors on a natural promoter in living cells. EMBO Reports 3: 1188-1194

Hager, G.L., Elbi, C. and Becker, M. (2002) Protein dynamics in the nuclear compartment . Current Opinion in Genetics and Development 12: 137-141 (Review)

Sheldon, L.A., Becker, M. and Smith, C.L. (2001) Steroid hormone receptor mediated histone deacetylation and transcription at the mouse mammary tumor virus promoter. J. Biol. Chem. 276: 32423-32426

Becker, M., Martin, E., Schneikert J., Krug, HF. and Cato A. C. (2000) Cytoplasmic localization and the choice of ligand determine aggregate formation by androgen receptor with amplified polyglutamine stretch. J. Cell Biol. 149: 255-262