A multiparametric anti-aging CRISPR screen uncovers a role for BAF in protein translation

Abstract

Progeria syndromes are very rare, incurable premature aging conditions recapitulating most aging features. Here, we report the first whole genome, multiparametric CRISPR anti-aging screen, identifying 43 new genes that can reverse multiple aging phenotypes in progeria. The screen was implemented in fibroblasts from Nestor-Guillermo Progeria Syndrome (NGPS) patients, carrying a homozygous p.Ala12Thr mutation in barrier-to-autointegration factor (BAF A12T). The hits were enriched for genes involved in protein translation, protein and RNA transport and osteoclast formation. We further confirmed that BAF A12T drives increased protein translation and translational errors that could directly contribute to premature aging in patients. This work has highlighted the power of multiparametric whole genome synthetic rescue screens to identify new anti-aging genes and uncover novel biology behind progeria-associated cellular dysfunction.

A progeria-associated BAF-1 mutation modulates gene expression and accelerates aging inC. elegans

“…We conclude that insertion of fluorescent tags has a dramatic effect in baf-1(G12T) nematodes as well as in flies (Duan et al 2023). Although further studies are needed to determine the molecular mechanism, we note that the high lethality of gfp::lmn-1; baf-1(G12T) embryos provides an ideal sensitized genetic background to screen for suppressors (Breusegem et al 2022). Tissue-specific DamID unveiled that BAF-1 bound predominantly to the distal arms of chromosomes, which are characterized by accumulation of repetitive elements and heterochromatin marks, in particular methylation of histone H3 on lysine 9 (Gerstein et al 2010;Ahringer and Gasser 2018).…”

“…We conclude that insertion of fluorescent tags has a dramatic effect in baf-1(G12T) nematodes as well as in flies (Duan et al 2023). Although further studies are needed to determine the molecular mechanism, we note that the high lethality of gfp::lmn-1; baf-1(G12T) embryos provides an ideal sensitized genetic background to screen for suppressors (Breusegem et al 2022).…”

“…The genes that changed both association with BAF-1 and expression level in the context of the G12T mutation might represent primary NGPS alterations. Importantly, translation levels and fidelity were observed to be altered in NGPS fibroblasts and depletion of ribosome components could improve several cellular parameters (Breusegem et al 2022).…”