Biology subjects

Scionti, I.

Publications and source records attributed to Scionti, I..

4 recordsLinked to original sources

bioRxiv2025

The AMPKa2/PHF2 axis is critical for turning over lipid droplets during muscle stem cell fate

Lipid metabolism is a key process required for muscle stem cell (MuSCs) function during regenerative myogenesis. However, the molecular pathway responsible of such regulation is still unknown. Studies of lysine demethylase PHF2 have reported its critical role in lipid metabolism in pathological processes, although there are no data regarding its role during MuSC fate transition. Here we show that PHF2 controls lipid droplet homeostasis in MuSCs during regenerative myogenesis, by promoting the contact between lipid droplets and mitochondria. Consistently, in absence of PHF2, myocytes accumulate lipid droplets, leading to mitochondrial dysfunction and impaired regeneration. Interestingly, such phenotype is rescued by AMPK2-PHF2 phospho-mimetic mutant expression. Our findings provide evidence that PHF2 is part of AMPK2 signaling and underscore the critical role of AMPK2/PHF2 axis in regulating lipid droplets homeostasis during MuSC fate.

cell biology↗

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↗

bioRxiv2022

Pharmacological inhibition of HDAC6 downregulates TGF-β via Smad2/3 acetylation and improves dystrophin-deficient muscles.

Abstract / SummaryThe absence of dystrophin in Duchenne muscular dystrophy (DMD) disrupts the dystrophin dystroglycan glycoprotein complex (DGC) resulting in fibers fragility and atrophy, associated with fibrosis and microtubules and neuromuscular junction (NMJ) disorganization. The specific non-conventional cytoplasmic histone deacetylase 6 (HDAC6) was previously shown to regulate acetylcholine receptor distribution and muscle atrophy. Here we show that administration of the HDAC6 specific inhibitor tubastatin A to the DMD mouse model mdx improves muscle strength, restores microtubules, NMJ and DGC organization, and reduces muscle atrophy and fibrosis. These effects involve the known action of HDAC6 on microtubules acetylation and muscle atrophy but also involve a yet undiscovered action of HDAC6 on transforming growth factor beta (TGF-{beta}) signaling. Conversely, to inhibitors of nuclear HDACs that regulate TGF-{beta} signaling via the activation of Follistatin expression, HDAC6 inhibition acts downstream of TGF-{beta} ligands and receptors by increasing Smad2/3 acetylation in the cytoplasm which in turn inhibits its phosphorylation and transcriptional activity.

physiology↗

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↗