P 2 - Prof. Dr. Roland Schüle

Prof. Dr. Roland Schüle

Klinik für Urologie / Zentrale Klinische Forschung

Universitätsklinikum Freiburg

Phone: +49 761 270-63100

Fax: 761-270-63110

roland.schuele@uniklinik-freiburg.de

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Project Summary

In the previous funding period we identified the protein kinase C (PKC) as a novel constituent of the LSD1/AR supercomplex and revealed that PKC signalling directs phosphorylation of LSD1 (LSD1ph). One phosphorylation-dependent function is assembly of LSD1 in a complex with CLOCK: BMAL1 transcription factors to play a pivotal role in circadian gene regulation. We uncovered that in the immediate vicinity to the phosphorylation site, LSD1 is methylated by the histone methyltransferase G9a/GLP in a ligand-dependent manner. Presence or absence of these posttranslational modifications on LSD1 (the “combinatorial code”) dictates recruitment or eviction of chromatin modifiers. To get insights in the molecular mechanisms controlled by the “combinatorial code” we shall test whether LSD1ph and LSD1me serve as signal-induced docking platforms for the assembly of chromatin modifiers that interpret and transduce the information, stored in these novel modifications into physiological traits. Consequently, we shall (i) decipher the LSD1 “combinatorial code” by structure-function and 3D crystal structure analyses of CHD1, JMJD2A or SWI/SNF in complex with LSD1. In addition, we shall (ii) characterise the function of the LSD1 combinatorial code in physiology and pathology by combining genome-wide binding and transcriptome analyses with genetically modified mouse
models.s.