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人类早衰症相关的 BAF-1 突变可调节基因表达并加速秀丽隐杆线虫的衰老。

A human progeria-associated BAF-1 mutation modulates gene expression and accelerates aging in C. elegans.

机构信息

Andalusian Centre for Developmental Biology, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Pablo de Olavide, Junta de Andalucía, Carretera de Utrera, km 1, 41013, Sevilla, Spain.

Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 14157, Sweden.

出版信息

EMBO J. 2024 Nov;43(22):5718-5746. doi: 10.1038/s44318-024-00261-8. Epub 2024 Oct 4.

DOI:10.1038/s44318-024-00261-8
PMID:39367234
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11574047/
Abstract

Alterations in the nuclear envelope are linked to a variety of rare diseases termed laminopathies. A single amino acid substitution at position 12 (A12T) of the human nuclear envelope protein BAF (Barrier to Autointegration Factor) causes Néstor-Guillermo Progeria Syndrome (NGPS). This premature ageing condition leads to growth retardation and severe skeletal defects, but the underlying mechanisms are unknown. Here, we have generated a novel in vivo model for NGPS by modifying the baf-1 locus in C. elegans to mimic the human NGPS mutation. These baf-1(G12T) mutant worms displayed multiple phenotypes related to fertility, lifespan, and stress resistance. Importantly, nuclear morphology deteriorated faster during aging in baf-1(G12T) compared to wild-type animals, recapitulating an important hallmark of cells from progeria patients. Although localization of BAF-1(G12T) was similar to wild-type BAF-1, lamin accumulation at the nuclear envelope was reduced in mutant worms. Tissue-specific chromatin binding and transcriptome analyses showed reduced BAF-1 association in most genes deregulated by the baf-1(G12T) mutation, suggesting that altered BAF chromatin association induces NGPS phenotypes via altered gene expression.

摘要

核膜的改变与各种罕见疾病有关，这些疾病被称为核纤层蛋白病。人类核包膜蛋白 BAF（自动整合因子的屏障）第 12 位（A12T）的单个氨基酸取代导致内斯特-古列尔莫早老症综合征（NGPS）。这种过早衰老的情况导致生长迟缓和严重的骨骼缺陷，但潜在的机制尚不清楚。在这里，我们通过修饰秀丽隐杆线虫中的 baf-1 基因座来模拟人类 NGPS 突变，从而产生了一种新的 NGPS 体内模型。这些 baf-1(G12T)突变线虫表现出与生育能力、寿命和抗应激能力相关的多种表型。重要的是，与野生型动物相比，baf-1(G12T)突变体在衰老过程中核形态的恶化速度更快，再现了早老症患者细胞的一个重要特征。尽管 BAF-1(G12T)的定位与野生型 BAF-1 相似，但突变体线虫中核膜上的 lamin 积累减少。组织特异性染色质结合和转录组分析表明，大多数由 baf-1(G12T)突变引起的基因失调的 BAF-1 关联减少，这表明改变的 BAF 染色质关联通过改变基因表达诱导 NGPS 表型。

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