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Acetylation-mediated phase control of the nucleolus regulates cellular acetyl-CoA responses

Houston, Ryan, Sekine, Shiori, Calderon, Michael J., Seifuddin, Fayaz, Wang, Guanghui, Kawagishi, Hiroyuki, Malide, Daniela A., Li, Yuesheng, Gucek, Marjan, Pirooznia, Mehdi, Nelson, Alissa J., Stokes, Matthew P., Stewart-Ornstein, Jacob, Wendell, Stacy G., Watkins, Simon C., Finkel, Toren, Sekine, Yusuke·2020
DOI 10.1101/2020.01.24.918706
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Abstract

Summary: The metabolite acetyl-CoA serves as an essential element for a wide range of cellular functions including ATP production, lipid synthesis and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which a cell responds to fluctuations in acetyl-CoA levels remain elusive. Here, we generate a cell system to selectively manipulate the nucleo-cytoplasmic levels of acetyl-CoA using CRISPR-mediated gene editing and acetate supplementation of the culture media. Using this system and quantitative omics analyses, we demonstrate that acetyl-CoA depletion alters the integrity of the nucleolus, impairing ribosomal RNA synthesis and evoking the ribosomal protein-dependent activation of p53. This nucleolar remodeling appears to be mediated through the class IIa HDAC deacetylases regulating the phase state of the nucleolus. Our findings highlight acetylation-mediated control of the nucleolus as an important hub linking acetyl-CoA fluctuations to cellular stress responses.

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  • Acetylation-mediated remodeling of the nucleolus is a primary driver of transcriptional activation in foundational cellular models.

    “Foundational cellular models demonstrate that acetylation-mediated remodeling of the nucleolus is a primary driver of transcriptional activation [178].”

    From Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators (2026) · cites this paper as [178]

    The Introduction (p. 5) says nucleolar remodeling after acetyl-CoA depletion leads to upregulation of p53, and the p53-activation section (p. 12) reports increased expression of several p53 target genes. This supports a specific stress-response pathway in the authors’ acetate-dependent cell model, not the broader claim that nucleolar remodeling is a primary driver of transcriptional activation. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Acetylation of lysine residues on histone tails reduces histone-DNA affinity, contributing to a more open chromatin configuration that facilitates transcriptional access to rDNA.

    “Acetylation of lysine residues on histone tails reduces the affinity between histones and DNA, contributing to a more open chromatin configuration that facilitates transcriptional access to rDNA [178,179].”

    From Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators (2026) · cites this paper as [178]

    The ‘Acetyl-CoA depletion modulates gene expressions’ section (p. 9) reports histone deacetylation alongside reduced transcription, supporting a general link between acetylation and transcription. The paper does not say that acetylation weakens histone–DNA affinity, opens chromatin, or thereby increases transcriptional access to rDNA; its nucleolar findings concern protein acetylation and nucleolar remodeling (pp. 14–15). (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Metadata

Authors
Houston, R., Sekine, S., Calderon, M. J., Seifuddin, F., Wang, G., Kawagishi, H., Malide, D. A., Li, Y., Gucek, M., Pirooznia, M., Nelson, A. J., Stokes, M. P., Stewart-Ornstein, J., Wendell, S. G., Watkins, S. C., Finkel, T., & Sekine, Y.
ORCID
Sekine, Yusuke
Publisher
openRxiv
Published
2020-01-25
DOI
10.1101/2020.01.24.918706
Type
Preprint
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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