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Updated: May 31, 2025
Characterizing Histone Post-translational Modification Alterations in Yeast Neurodegenerative Proteinopathy Models
Published on: March 24, 2019
Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification
Seth A Bennett1,2, Samantha N Cobos1,3, Raven M A Fisher1,2
1Department of Chemistry and Biochemistry, Brooklyn College, Brooklyn, NY 11210, USA.
Abstract:
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative disorders sharing pathological and genetic features, including mutations in the FUS gene. FUS is an RNA-binding protein that mislocalizes to the cytoplasm and aggregates in ALS/FTD. In a yeast model, FUS proteinopathy is connected to changes in the epigenome, including reductions in the levels of H3S10ph, H3K14ac, and H3K56ac. Exploiting the same model, we reveal novel connections between FUS aggregation and epigenetic dysregulation. We show that the histone-modifying enzymes Ipl1 and Rtt109-responsible for installing H3S10ph and H3K56ac-are excluded from the nucleus in the context of FUS proteinopathy. Furthermore, we found that Ipl1 colocalizes with FUS, but does not bind it directly. We identified Nop1 and Rrp5, a histone methyltransferase and rRNA biogenesis protein, respectively, as FUS binding partners involved in the growth suppression phenotype connected to FUS proteinopathy. We propose that the nuclear exclusion of Ipl1 through indirect interaction with FUS drives the dysregulation of H3S10ph as well as H3K14ac via crosstalk. We found that the knockdown of Nop1 interferes with these processes. In a parallel mechanism, Rtt109 mislocalization results in reduced levels of H3K56ac. Our results highlight the contribution of epigenetic mechanisms to ALS/FTD and identify novel targets for possible therapeutic intervention.
Insights
FUS protein aggregation in neurodegenerative diseases like ALS and FTD disrupts epigenetics. This study reveals how FUS causes nuclear exclusion of key enzymes, leading to altered histone marks and potential therapeutic targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases.
- Mutations in the FUS gene are linked to ALS and FTD, causing FUS protein to mislocalize and aggregate.
- FUS proteinopathy is associated with epigenetic changes, including reduced histone modifications like H3S10ph, H3K14ac, and H3K56ac.
Purpose of the Study:
- To investigate the novel connections between FUS aggregation and epigenetic dysregulation in a yeast model.
- To identify the mechanisms by which FUS aggregation impacts histone modification levels.
- To explore potential therapeutic targets for ALS and FTD based on epigenetic alterations.
Main Methods:
- Utilized a yeast model of FUS proteinopathy.
- Assessed the localization of histone-modifying enzymes (Ipl1, Rtt109) in the presence of FUS aggregation.
- Identified FUS binding partners (Nop1, Rrp5) using genetic and biochemical approaches.
- Investigated the impact of FUS binding partners and histone modification changes on cellular phenotypes.
Main Results:
- FUS aggregation led to the nuclear exclusion of histone-modifying enzymes Ipl1 and Rtt109.
- Ipl1 was found to colocalize with FUS, suggesting indirect interaction.
- Nop1 and Rrp5 were identified as FUS binding partners contributing to growth suppression.
- Nuclear exclusion of Ipl1 indirectly caused dysregulation of H3S10ph and H3K14ac.
- Rtt109 mislocalization resulted in reduced H3K56ac levels.
- Nop1 knockdown interfered with these epigenetic processes.
Conclusions:
- FUS proteinopathy drives epigenetic dysregulation through the nuclear exclusion of key histone-modifying enzymes.
- Indirect interactions involving FUS and specific binding partners mediate these epigenetic alterations.
- These findings highlight the role of epigenetics in ALS/FTD pathogenesis.
- Identified novel targets (Nop1, Rrp5, Ipl1, Rtt109) for potential therapeutic interventions in ALS and FTD.
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