LSD1 AND PHF2 ROLE IN MUSCLE STEM CELL ACTIVATION AND SKELETAL MUSCLE REGENERATION

LSD1 AND PHF2 ROLE IN MUSCLE STEM CELL ACTIVATION AND SKELETAL MUSCLE REGENERATION Skeletal muscle is the largest tissue mass of the body and it is necessary for locomotion and support, it is composed by a multinucleate myofibers syncytia formed by mononuclear progenitor cells fusion [Chal et al. 2017]. Skeletal muscle repair system is necessary to maintain muscle homeostasis upon injury and relies on adult muscle stem cells (MuSC), after injury MuSCs get activated and they can both engage into commitment and differentiation or decide to self-renew repopulating the stem cell niche [Yang et al. 2018]. LSD1 is an amine oxidase and a Flavin-containing protein which specifically demethylates histone 3 tail, through a FAD-dependent reaction. [Yang et al. 2006]. It is known that elevated level of LSD1 supports skeletal myocyte progression in muscle regeneration after injury [Tosic et al 2018]. It has been demonstrated that LSD1 interacts with MyoD, a key regulator for the muscle progenitor cells engagement, to remove the repression histone mark H3K9me2 from MyoG promoters and its ablations impairs myogenesis [Choi et al 2010]. PHF2 contains a PHD finger domain and is an epigenetic regulator which de-methylates lysine 9 in histone 3 followed by transcription activation of target genes [Baba et al. 2011] PHF2 promotes H3K9me2 demethylation in regulation of metabolic and anti-oxidative gene programs against liver inflammation, oxidative stress and fibrosis development [Bricambert et al. 2018]. We know that the JAK/STAT pathway is implicated in myoblast proliferation [ Wang et al. 2008] and progenitor commitment. Moreover, MyoD upregulation depends on STAT3-phosphorilated state [Tierney et al. 2014]. The aim of this thesis is to address the role of both LSD1 and PHF2 in muscle stem cell plasticity and in the STAT3 signaling pathway in a physiological context of skeletal muscle regeneration. We asked if the absence of LSD1 and PHF2 in muscle stem cells could play a role during muscle regeneration compared with the control. Our results suggest that at 7dpi there is an increase of MYOD protein level in LSD1 SCiKO and PHF2 SCiKO compared with the 3dpi, these findings support the hypothesis that ablation of LSD1 or PHF2 leads to a delay of muscle stem cell commitment. However, there is no significant changes in the phosphorylation rate of STAT3. Thus, we can conclude that in LSD1 and PHF2 KO muscle stem cells there is a delay in the cell commitment during regeneration compared to the control and we can also speculate that LSD1 or PHF2 are not affecting the STAT3 signaling pathway.