A progeria-associated BAF-1 mutation modulates gene expression and accelerates aging in C. elegans I
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), reproducing 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 the two proteins resembled each other, we also identified many discrete regions with altered association to BAF-1(G12T). 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 propose that C. elegans can serve as a relevant model to understand how a mutation in an essential protein expressed throughout development triggers the appearance of symptoms ~2 years after birth of human patients. Overall design: Tissue-specific RNA polymerase DamID in hypodermis and intestine of C. elegans to determine transcriptomes of wild type and baf-1(G12T) mutants.