Final Report Summary - LSD1 (The lysine-specific demethylase1 (LSD1) in physiology and pathology)
In this project we uncovered yet unknown physiological and pathological function of LSD1. LSD1 serves diverse roles in muscle and adipose tissue (WAT). In vivo WAT Lsd1 is required for WAT differentiation since Lsd1 knockout using Fatty acid binding protein 4 (Fabp4)-Cre deleter strain led to complete absence of visceral and subcutaneous fat in mice. In addition, LSD1 is necessary to maintain oxidative and thermogenic capacities of beige adipocytes in WAT. Age-dependent decline of Lsd1 is responsible for the conversion of beige adipocytes into white inguinal and epididymal WAT during aging. Similarly, ablation or enzymatic inhibition of Lsd1 in brown adipocytes leads to metabolic reprogramming and induces whitening of brown adipose tissue. Altogether, our data show that Lsd1 governs cell type specific alternative transcriptional repertoires most probably via the action of different tissue-specific Lsd1 containing complexes and/or target genes. Furthermore, our results implicate that physiological levels of Lsd1 are necessary for normal muscle regeneration after injury. Elevated levels of Lsd1 might be beneficial and accelerate the process of muscle regeneration, whereas loss or inhibition of Lsd1 leads to aberrant differentiation and acquisition of a brown fat phenotype. Lsd1 therefore, not only promotes muscle differentiation, but also restricts the fate of satellite cells to the myogenic lineage. Understanding the molecular underpinnings by which Lsd1 regulates the myogenic-adipogenic switch might open novel therapeutic perspectives for muscle regeneration from injury caused by trauma or degeneration in muscle dystrophies and aging. In pathological situations such as cancer we unravelled the important role of LSD1. Our data suggested that pharmacological impairment of LSD1 function might provide novel therapeutic opportunities. Consequently, we set up a search expedition for optimised inhibitors of LSD1 and developed in a collaborative effort within the CRC992 and pharmaceutical partners a reversible LSD1 inhibitor with nanomolar potency and efficacy both in vitro and in vivo. This inhibitor is now clinical phase I studies.