A progeria-associated BAF-1 mutation modulates gene expression and accelerates aging in C. elegans
crossref(2024)
Abstract
Alterations in the nuclear envelope are linked to a variety of rare diseases termed laminopathies. These include both tissue specific and systemic diseases. A single amino acid substitution in human barrier to autointegration factor (BAF) at position 12 (A12T) causes Néstor-Guillermo Progeria Syndrome (NGPS). This premature ageing condition affects a variety of tissues, leading to growth retardation and severe skeletal defects, including scoliosis. Taking advantage of the conservation between human and C. elegans BAF proteins, we have modified the baf-1 locus in C. elegans to mimic the human NGPS mutation ( baf-1(G12T) ). In this work, we characterized the phenotypes caused by the G12T mutation at molecular, cellular, and organismal scale. We found that the mutation induced multiple phenotypes related to fertility, lifespan, and stress resistance. Importantly, nuclear morphology deteriorated faster during aging in baf-1(G12T) , relative to wild-type animals, coinciding with an important hallmark of cells from progeria patients. Nuclear envelope accumulation of lamin and emerin was reduced whereas localization of BAF-1(G12T) was similar to wild-type BAF-1. We determined the chromatin binding profiles for wild-type and mutant BAF-1 and performed transcriptome analyses through tissue-specific DamID. Although the global profiles for wild-type and G12T BAF-1 resembled one another, we also identified many discrete regions with altered BAF-1(G12T) association. Most genes deregulated by the baf-1(G12T) mutation were characterized by a change in BAF-1 association, suggesting a direct relation between BAF-1 binding and gene expression. We conclude that C. elegans is a relevant model to understand how a mutation in an essential protein expressed throughout development triggers the appearance of symptoms in early childhood.
### Competing Interest Statement
The authors have declared no competing interest.
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