Lacoste, N. | bioRxiv Science

bioRxiv2022

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

The Wnt/{beta}-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/{beta}-Catenin signaling to chromatin modifications has been a challenge over the past decades. Functional studies of the histone 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 {beta}-Catenin is a substrate of LSD1. Demethylation by LSD1 prevents {beta}-Catenin degradation thereby maintaining its nuclear levels. Consistently, in absence of LSD1, {beta}-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 {beta}-Catenin protein stabilization. Altogether, by inscribing LSD1 and {beta}-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/{beta}-Catenin signaling and LSD1 on stem cell fate.

developmental biology↗

bioRxiv2019

H2A.Z is dispensable for both basal and activated transcription in post-mitotic mouse muscles

The histone variant H2A.Z is enriched in nucleosomes surrounding the transcription start site of active promoters, suggesting that it might be implicated in transcription. It is also required during mitosis. However, evidences obtained so far mainly rely on correlative evidences obtained in actively dividing cells. We have defined a paradigm in which cell cycle cannot interfere with H2A.Z transcriptional studies by developing an in vivo systems to invalidate H2A.Z in terminally differentiated post-mitotic muscle cells to dissociate its role during transcription from its role during mitosis. ChIP-seq, RNA-seq and ATAC-seq experiments performed on H2A.Z KO post-mitotic muscle cells show that this histone variant is neither required to maintain nor to activate transcription. Altogether, this study provides in vivo evidence that in the absence of mitosis H2A.Z is dispensable for transcription and that the enrichment of H2A.Z on active promoters is rather a marker than an actor of transcriptional activity.

cell biology↗