Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity.
Giorgia Maria FerlazzoAnna Maria GambettaSonia AmatoNoemi CannizzaroSilvia AngiolilloMattia ArboitLinda DiamanteElena CarbogninPatrizia RomaniFederico La TorreElena GalimbertiFlorian PflugMirko LuoniSerena GiannelliGiuseppe PepeLuca CapocciAlba Di PardoPaola VanzaniLucio ZennaroVania BroccoliMartin LeebEnrico MoroVittorio MaglioneGraziano MartelloPublished in: Nature communications (2023)
Huntington's disease (HD) is a neurodegenerative disorder caused by CAG-repeat expansions in the huntingtin (HTT) gene. The resulting mutant HTT (mHTT) protein induces toxicity and cell death via multiple mechanisms and no effective therapy is available. Here, we employ a genome-wide screening in pluripotent mouse embryonic stem cells (ESCs) to identify suppressors of mHTT toxicity. Among the identified suppressors, linked to HD-associated processes, we focus on Metal response element binding transcription factor 1 (Mtf1). Forced expression of Mtf1 counteracts cell death and oxidative stress caused by mHTT in mouse ESCs and in human neuronal precursor cells. In zebrafish, Mtf1 reduces malformations and apoptosis induced by mHTT. In R6/2 mice, Mtf1 ablates motor defects and reduces mHTT aggregates and oxidative stress. Our screening strategy enables a quick in vitro identification of promising suppressor genes and their validation in vivo, and it can be applied to other monogenic diseases.
Keyphrases
- genome wide
- oxidative stress
- cell cycle arrest
- cell death
- induced apoptosis
- dna methylation
- copy number
- endoplasmic reticulum stress
- transcription factor
- embryonic stem cells
- pi k akt
- ischemia reperfusion injury
- diabetic rats
- dna damage
- endothelial cells
- poor prognosis
- binding protein
- wild type
- signaling pathway
- gene expression
- adipose tissue
- long non coding rna
- oxide nanoparticles
- cell proliferation
- mesenchymal stem cells
- amino acid
- bone marrow