Charakterisierung der Histondemethylase LSD1

• Antragsteller: Professor Dr. Roland Schüle
• Fachliche Zuordnung: Hämatologie, Onkologie
• Förderung: Förderung von 2006 bis 2012
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 29856875

• Erstellungsjahr: 2014

Zusammenfassung der Projektergebnisse

The data we generated in this funding period allowed us proceed major steps forward in understanding the physiology and pathology of LSD1. The powerful tool of combining detailed in vitro studies with genome-wide analyses and various animal models allowed us to decipher novel aspects of LSD1 biology. Clearly, we are only at the beginning and much more knowledge needs to be learned. Consequently, this project put us in a position to initiate additional genetically modified LSD1 mouse models. Consequently, to further evaluate tissue-restricted functions we deleted Lsd1 by crossing the conditional Lsd1 allele to well described Cre deleter strains, which robustly and specifically facilitate Cre-mediated deletion of LSD1 in testis, ovary, skin, muscle, liver, white fat, brown fat, and brain. The analysis of the stunning phenotypes of these tissue-specific KO animals is ongoing and will further pioneer our knowledge on the physiological and pathological function of LSD1.

Projektbezogene Publikationen (Auswahl)

• (2007) Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptordependent gene expression. Nature Cell Biology 9, 347-353
  Wissmann, M., Yin, N., Müller, J.M., Greschik, H., Fodor, B.D., Jenuwein, T., Vogler, C., Schneider, R., Günther, T., Buettner, R., Metzger, E. and Schüle, R.
  
• (2008) A TFTC/STAGA module mediates histone H2A and H2B deubiquitination, nuclear receptor activation and counteracts heterochromatin silencing. Mol. Cell 29, 92-101
  Zhao, Y., Lang, G., Ito, S., Bonnet, J., Metzger, E., Sawatsubashi, S., Suzuki, E., Le Guezennec, X., Stunnenberg, H.G., Krasnov, A., Georgieva, S., Schüle, R., Takemaya, K-I., Kato, S., Tora, L. and Devys, D.
  
• (2008) Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation. Nature Cell Biology 10, 53-60
  Metzger, E., Yin, N., Wissmann, M., Kunowska, N., Fischer, K., Friedrichs, N., Patnaik, D., Higgins, J.M.G., Potier, N., Scheidtmann, K.H., Buettner, R. and Schüle, R.
  
• (2009) Lysine-Specific Demethylase 1 Is Strongly Expressed in Poorly Differentiated Neuroblastoma: Implications for Therapy. Cancer Res. 69, 2065-2071
  Schulte J.H., Lim, S., Schramm, A., Friedrichs, N., Koster, J., Versteeg, R., Ora, I., Pajtler, K., Klein-Hitpass, L., Kuhfittig-Kulle, S., Metzger, E., Schüle, R., Eggert, A., Buettner, R. and Kirfel, J.
  
• (2010) PELP1 is a reader of histone H3 methylation that facilitates oestrogen receptor-alpha target gene activation by regulating lysine demethylase 1 specificity. EMBO Rep. 11, 438-44
  Nair, SS., Nair, B.C., Cortez, V., Chakravarty, D., Metzger, E., Schüle, R., Brann, D.W., Tekmal, R.R. and Vadlamudi, R.K.
  
• (2010) Phosphorylation of histone H3T6 by PKCbI controls demethylation at histone H3K4. Nature 464, 792-796
  Metzger, E., Imhof, A., Patel, D., Kahl, K., Hoffmeyer, K., Friedrichs, F., Müller, J.M., Greschik, H., Kirfel, J., Ji, S., Kunowska, N., Beisenherz-Huss, C., Günther, T., Buettner, R. and Schüle, R.
  
• (2011) Lysine-specific demethylase 1 is highly expressed in solitary fibrous tumors, synovial sarcomas, rhabdomyosarcomas, desmoplastic small round cell tumors, and malignant peripheral nerve sheath tumors. Human Pathology 42, 1667-1675
  Schildhaus, H.U., Riegel, R., Hartmann, W., Steiner, S., Wardelmann, E., Merkelbach-Bruse, S., Tanaka, S., Sonobe, H., Schüle, R., Buettner, R. and Kirfel, J.
  
• (2012) Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation. Leukemia 26, 2039-2051
  Sprüssel, A., Schulte, J.H., Weber, S., Necke, M., Händschke, K., Thor, T., Pajtler, K.W., Schramm, A., König, K., Diehl, L., Mestdagh, P., Vandesompele, J., Speleman, F., Jastrow, H., Heukamp, L.C., Schüle, R., Dührsen, U., Buettner, R., Eggert, A. and Göthert, J.R.
  
• (2012). Impairment of prostate cancer cell growth by a selective and reversible lysinespecific demethylase 1 inhibitor. Int. J. Cancer 131, 2704-2709
  Willmann, D., Lim, S., Wetzel, S., Metzger, E., Jandausch, A., Wilk, W., Jung, M., Forne, I., Imhof, A., Janzer, A., Kirfel, J., Waldmann, H., Schüle, R. and Buettner, R.
  (Siehe online unter https://doi.org/10.1002/ijc.27555)
• (2014) LSD1 promotes oxidative metabolism of white adipose tissue. Nat. Commun. 5, 4093
  Duteil, D., Metzger,E., Willmann, D., Karagianni, P., Friedrichs, N., Greschik, H., Günther,T., Buettner, R., Talianidis, I., Metzger, D. and Schüle, R.
  (Siehe online unter https://doi.org/10.1038/ncomms5093)
• (2014) Lsd1 regulates differentiation onset and migration of trophoblast stem cells Nat. Commun. 5, 3174-3184
  Zhu, D., Hölz, S., Metzger, E., Pavlovic, M., Jandausch, A., Jilg, C., Galgoczy, P., Herz, C., Moser, M., Metzger, D., Günther, T., Arnold, S.J. and Schüle, R.
  
• (2014) Phosphorylation of LSD1 by PKCα Is Crucial for Circadian Rhythmicity and Phase Resetting. Mol. Cell 53, 791-805
  Nam, H.J., Boo, K., Kim, D.H., Choe, H.K., Kim, C.R., Sun, W., Kim, H., Kim, K., Lee, H., Schüle, R., Yoo, S-H., Takahashi, J.S., Cho, S., Son, G.H. and Baek, S.H.
  (Siehe online unter https://doi.org/10.1016/j.molcel.2014.01.028)