LSD1-mediated demethylation of β-catenin regulates muscle stem cell self-renewal potential

• Published in: bioRxiv
• Main Authors: Mouradian, Sandrine, Cicciarello, Delia, Lacoste, Nicolas, Berretta, Francesca, Schaeffer, Laurent, Scionti, Isabella
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 12.06.2022
• Subjects: Cell fate; Cell self-renewal; Chromatin; Demethylation; Epigenetics; Gene expression; Histones; MyoD protein; Stem cells; Wnt protein; β-Catenin
• DOI: 10.1101/2022.06.10.495614

The Wnt/β-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/β-Catenin signaling to chromatin modifications has been a challenge over the past decades. Functional studies of the histone demethylase KDM1a/LSD1 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 β-Catenin is a substrate of LSD1. Demethylation by LSD1 prevents β-Catenin degradation thereby increasing its nuclear levels. In muscle stem cells, β-Catenin and LSD1 are both recruited on the MyoD Core Enhancer to control MyoD expression and promote muscle stem cell commitment. Moreover, a β-Catenin reporter construct shows that the involvement of LSD1 in β-Catenin regulation is not restricted to MyoD activation. Altogether, by inscribing them in the same molecular cascade linking extracellular factors to epigenetic modifications and gene expression, our results provide a rational explanation to the similarity of action of canonical Wnt signaling and LSD1 on cell fate. Competing Interest Statement The authors have declared no competing interest.