A Progeria-Associated Mutation in the Chromatin Binding Protein BAF-1 Alters Gene Expression and Accelerates Aging in C. elegans

Core Concepts

A single amino acid substitution (G12T) in the chromatin binding protein BAF-1 in C. elegans, mimicking the human Néstor-Guillermo Progeria Syndrome (NGPS) mutation, leads to altered gene expression, accelerated deterioration of nuclear morphology, and changes in stress resistance, providing a relevant model to study the mechanisms underlying progeria.

Abstract

The authors investigated the effects of the progeria-associated G12T mutation in the C. elegans BAF-1 protein, which is homologous to the human BAF protein. They found that the baf-1(G12T) mutation:

Reduces brood size and lifespan in a temperature-dependent manner. The mutant worms exhibit reduced fertility, with many unfertilized oocytes, due to defects in sperm function.

Accelerates the age-dependent deterioration of nuclear morphology in hypodermal cells, with more nuclei displaying irregular shapes compared to wild-type.

Reduces the accumulation of lamin and emerin at the nuclear envelope, suggesting the mutation weakens the interaction between BAF-1 and these nuclear envelope components.

Leads to widespread changes in BAF-1 chromatin binding profiles in the hypodermis and intestine, with many genes showing differential association with wild-type versus mutant BAF-1.

Results in the deregulation of genes involved in ribosome biogenesis and cuticle structure, which correlates with the altered chromatin binding of BAF-1(G12T).

Causes increased sensitivity to UV irradiation and heat stress, but paradoxically enhanced resistance to oxidative stress, suggesting complex organismal responses to the progeria-associated mutation.

The authors conclude that the baf-1(G12T) mutant in C. elegans is a relevant model to study the mechanisms by which a single amino acid substitution in an essential chromatin binding protein can trigger the appearance of progeria-like symptoms.

Stats

The baf-1(G12T) mutation reduces the brood size of hermaphrodites by 66% at 25°C compared to wild-type.
The median lifespan of baf-1(G12T) mutants is reduced by 7-9% compared to wild-type at 25°C.
The frequency of class I+II nuclei (with smooth, regular nuclear envelope) decreases from 90% in wild-type to 27-42% in baf-1(G12T) by day 6 of adulthood at 25°C.
13 out of 129 genes deregulated in the intestine of baf-1(G12T) mutants encode ribosomal proteins.
7 out of 8 downregulated ribosomal protein genes show higher association with BAF-1(G12T) compared to wild-type BAF-1.

Quotes

"The baf-1(G12T) mutation induced multiple phenotypes related to fertility, lifespan, and stress resistance."
"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."
"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."

Key Insights Distilled From

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

by Romero-Bueno... at www.biorxiv.org 03-17-2024

https://www.biorxiv.org/content/10.1101/2024.03.17.585430v1

Deeper Inquiries

How do the tissue-specific changes in BAF-1 chromatin binding profiles contribute to the diverse phenotypes observed in the baf-1(G12T) mutants?

The tissue-specific changes in BAF-1 chromatin binding profiles play a crucial role in the diverse phenotypes observed in the baf-1(G12T) mutants. The altered chromatin association of BAF-1 and BAF-1(G12T) in different tissues, such as the hypodermis and intestine, can lead to differential regulation of gene expression. This differential binding can impact the expression of specific genes involved in various cellular processes, ultimately contributing to the phenotypic changes observed in the mutants. For example, the enrichment of BAF-1(G12T) in chromosome centers in the hypodermis suggests a potential impact on chromatin organization and gene expression in this tissue. The tissue-specific interactions of BAF-1 with predominantly silent genes, as observed in the study, can further modulate cellular functions and pathways, leading to the manifestation of distinct phenotypes in different tissues.

How do the underlying mechanisms lead to the paradoxical effects of the baf-1(G12T) mutation on stress resistance, with increased sensitivity to UV and heat but enhanced tolerance to oxidative stress?

The paradoxical effects of the baf-1(G12T) mutation on stress resistance, with increased sensitivity to UV and heat but enhanced tolerance to oxidative stress, can be attributed to the complex interplay of cellular pathways and responses affected by the mutation. The mutation likely disrupts key mechanisms involved in stress response and repair processes, leading to the observed phenotypic outcomes.
The increased sensitivity to UV and heat stress in baf-1(G12T) mutants may result from impaired DNA repair mechanisms, compromised protein folding and stability, or dysregulated stress response pathways. The mutation could interfere with the proper functioning of DNA repair enzymes, leading to accumulation of DNA damage and increased susceptibility to UV-induced lesions. Similarly, the mutation may disrupt protein homeostasis and chaperone-mediated folding, making the mutants more vulnerable to heat-induced protein misfolding and aggregation.
On the other hand, the enhanced tolerance to oxidative stress in baf-1(G12T) mutants could be due to alterations in antioxidant pathways or stress response mechanisms. The mutation may activate specific pathways that counteract oxidative damage, leading to improved survival under oxidative stress conditions. Additionally, the mutation might modulate cellular redox balance or signaling pathways that promote cell survival in the presence of oxidative stressors.
Overall, the paradoxical effects of the baf-1(G12T) mutation on stress resistance likely stem from its multifaceted impact on cellular processes involved in stress response, DNA repair, protein homeostasis, and redox regulation.

Could the baf-1(G12T) mutant C. elegans model be used to screen for suppressor mutations or therapeutic interventions that could ameliorate the progeria-like symptoms?

Yes, the baf-1(G12T) mutant C. elegans model holds great potential for screening suppressor mutations or therapeutic interventions that could ameliorate the progeria-like symptoms associated with the mutation. The model provides a valuable platform to study the molecular mechanisms underlying premature aging and to identify genetic modifiers or pharmacological targets that could mitigate the effects of the mutation.
By conducting genetic screens in the baf-1(G12T) mutant worms, researchers can identify suppressor mutations that restore normal cellular functions, improve stress resistance, or delay the onset of aging-related phenotypes. These suppressor mutations could pinpoint key pathways or genes that interact with BAF-1 and modulate its function, offering insights into potential therapeutic targets for progeria and related conditions.
Furthermore, the C. elegans model can be utilized for high-throughput drug screening to identify compounds that rescue the phenotypic defects associated with the baf-1(G12T) mutation. Small molecule screens in the mutant worms can reveal candidate compounds that target specific pathways affected by the mutation, providing leads for the development of therapeutic interventions for progeria and age-related disorders.
In conclusion, the baf-1(G12T) mutant C. elegans model offers a versatile platform for exploring genetic and pharmacological strategies to counteract the progeria-like symptoms induced by the mutation, paving the way for potential therapeutic advancements in the field of premature aging research.