LSD1 · The lysine-specific demethylase1 (LSD1) in physiology and pathology

The identification of the first histone demethylase lysine-specific demethylase 1 (LSD1) established not only the concept of reversible histone methylation in epigenetic regulation but also translated this fundamentally novel biological observation into understanding the molecular mechanisms regulation stemness, differentiation, proliferation, and pathological growth. To unravel in an unbiased and comprehensive manner the biological function of LSD1 in physiology and pathology, we developed LSD1-deficient and LSD1-transgenic mouse models. LSD1-transgenic animals develop prostate tumours demonstrating that increased expression of LSD1 suffices for oncogenic growth in vivo. In addition, LSD1-transgenic animals exhibit a metabolic shift towards overt obesity in adulthood. LSD1-deficiency causes early embryonic lethality around day 7.5 of development. However, deletion of LSD1 is not essential for the development of the embryo proper until the onset of gastrulation, suggesting that the early embryonic lethality is caused by trophoblast defects. Indeed, our data demonstrate that LSD1 is crucial for maintaining trophoblast stem cells in their niche and required for the specification of trophoblast stem cell fate during initial steps of differentiation. To identify the underlying mechanisms that allow LSD1 to control a wide range of biological systems such as trophoblast stem cell fate in the early embryo, obesity, and prostate tumourigenesis in the adult, we propose to a) identify LSD1-associated protein complexes and b) LSD1 target genes establishing these phenotypes in the mouse. In addition, we shall uncover c) signalling pathways that modify LSD1 in these phenotypes allowing us to explore the therapeutic potential of targeting these signalling pathways.""