LSD1 controls a nuclear checkpoint in Wnt/ß-Catenin signaling to regulate muscle stem cell self-renewal.

The Wnt/ß-Catenin pathway plays a key role in cell fate determination during development and in adult tissue regeneration by stem cells. These processes involve profound gene expression and epigenome remodeling and linking Wnt/ß-Catenin signaling to chromatin modifications has been a challenge over the past decades. Functional studies of the lysine demethylase LSD1/KDM1A converge to indicate that this epigenetic regulator is a key regulator of cell fate, although the extracellular cues controlling LSD1 action remain largely unknown. Here we show that ß-Catenin is a substrate of LSD1. Demethylation by LSD1 prevents ß-Catenin degradation thereby maintaining its nuclear levels. Consistently, in absence of LSD1, ß-Catenin transcriptional activity is reduced in both MuSCs and ESCs. Moreover, inactivation of LSD1 in mouse muscle stem cells and embryonic stem cells shows that LSD1 promotes mitotic spindle orientation via ß-Catenin protein stabilization. Altogether, by inscribing LSD1 and ß-Catenin in the same molecular cascade linking extracellular factors to gene expression, our results provide a mechanistic explanation to the similarity of action of canonical Wnt/ß-Catenin signaling and LSD1 on stem cell fate.

[The unexpected role of lipid droplets in the regulation of muscle stem cells fate]. / Le rôle inattendu des gouttelettes lipidiques dans la régulation du destin des cellules souches musculaires.

Muscle stem cells (MuSCs) are skeletal muscle resident stem cells responsible of skeletal muscle regeneration and tissue integrity maintenance. It is now becoming prominent that the ability of MuSCs either to self-renew or differentiate is affected by cellular metabolism. Recently, a study elucidated that lipid droplets (LDs) are novel key regulators of MuSC fate. Indeed, LDs distribute differently depending on MuSC state during the regeneration process, as LDLow MuSCs are more proned to self-renew while LDHigh MuSCs commit to differentiation. Therefore, these findings highlight that the LD turnover is necessary for MuSC fate decision, opening the question of the molecular mechanism underlying lipid metabolism regulation of MuSC fate determination.

Title: Le rôle inattendu des gouttelettes lipidiques dans la régulation du destin des cellules souches musculaires. Abstract: Les cellules souches musculaires (CSM) sont des cellules souches résidentes du muscle squelettique responsables de la régénération de ce dernier. Il est de plus en plus évident que la capacité des CSM à s'auto-renouveler ou à se différencier est influencée par le métabolisme cellulaire. Une nouvelle étude a récemment établi que les gouttelettes lipidiques (GL) sont de nouveaux régulateurs du devenir des CSM. En effet, les GL se répartissent différemment selon l'état des CSM au cours du processus de régénération, les CSM avec peu de GL étant plus enclines à s'auto-renouveler tandis que les CSM contenant beaucoup de GL s'engagent dans la différenciation. Ces résultats soulignent que le renouvellement correct des GL est nécessaire pour décider du destin des CSM. Ceci pose la question du mécanisme moléculaire sous-jacent de la régulation du métabolisme des lipides dans la détermination du destin des CSM.

Epigenetic Control of Muscle Stem Cells: Focus on Histone Lysine Demethylases.

Adult skeletal muscle is mainly composed of post-mitotic, multinucleated muscle fibers. Upon injury, it has the unique ability to regenerate thanks to the activation of a subset of quiescent muscle stem cells (MuSCs). Activated MuSCs either differentiate to repair muscle, or self-renew to maintain the pool of MuSC. MuSC fate determination is regulated by an intricate network of intrinsic and extrinsic factors that control the expression of specific subsets of genes. Among these, the myogenic regulatory factors (MRFs) are key for muscle development, cell identity and regeneration. More globally, cell fate determination involves important changes in the epigenetic landscape of the genome. Such epigenetic changes, which include DNA methylation and post-translational modifications of histone proteins, are able to alter chromatin organization by controlling the accessibility of specific gene loci for the transcriptional machinery. Among the numerous epigenetic modifications of chromatin, extensive studies have pointed out the key role of histone methylation in cell fate control. Particularly, since the discovery of the first histone demethylase in 2004, the role of histone demethylation in the regulation of skeletal muscle differentiation and muscle stem cell fate has emerged to be essential. In this review, we highlight the current knowledge regarding the role of histone demethylases in the regulation of muscle stem cell fate choice.