Dynamic Changes of Histone H1 Variants in Drug-Induced Senescence.
- 1Molecular Biology Institute of Barcelona (IBMB-CSIC), 08028 Barcelona, Spain.
Abstract
Background/Objectives: Cellular senescence is a stress-induced state of irreversible cell cycle arrest triggered by diverse molecular stimuli. It is characterized by distinct phenotypic alterations, including the senescence-associated secretory phenotype (SASP), profound chromatin remodeling, and morphological changes. While senescent cells accumulate during physiological aging, they are also prevalent in pathological contexts such as cancer. Histone H1 is a crucial regulator of chromatin organization and gene expression, and emerging evidence suggests that its content and nuclear distribution change dynamically during senescence. Methods: Here, we investigated the expression and localization dynamics of six somatic H1 variants (H1.0, H1.2 to H1.5, and H1X) upon senescence induction in T47D breast cancer cells, evaluating their correlation with chromatin structural alterations, repetitive element expression, and interferon response activation. Senescence was triggered using doxorubicin, a topoisomerase inhibitor, among other drugs tested, which was confirmed by the accumulation of standard senescence markers (ß-galactosidase activity, p21CIP1/WAF1, H3K9me3, and γH2AX). Results: We observed variant-specific expression patterns, suggesting distinct functional contributions to senescence. Specifically, H1.0 was upregulated, whereas H1.3, H1.4 and H1.5 were downregulated. Furthermore, the nuclear redistribution of H1.2, H1.3, and H1.5 points to their active roles in local gene expression and silencing. These alterations coincided with the increased transcription of repetitive elements (LINEs, SINEs, LTRs and satellites) and the elevated expression of interferon-stimulated genes (IFI27, OASL, IFIT3), likely driven by localized chromatin decompression. Finally, functional knock-down experiments revealed that while the depletion of individual H1 variants yielded distinct cellular effects, it neither sufficed to fully mimic drug-induced senescence nor significantly altered the cellular response to senescence-inducing drugs. Conclusions: Taken together, our findings indicate that while H1 variant deregulation may be a hallmark of senescent breast cancer cells, and linker histones may actively modulate the threshold for senescence induction and genotoxic response, it represents one component of a broader, coordinated chromatin remodeling program.
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BibTeX
@article{mittag2026dynamic,
title = {{Dynamic Changes of Histone H1 Variants in Drug-Induced Senescence.}},
author = {Nora Mittag and Adriana Birbio and Olga Delipetridou and Pau Homs-Aguadé and Carles Bonet-Costa and Albert Jordan},
journal = {Genes},
year = {2026},
month = oct,
doi = {10.3390/genes17101274},
url = {https://europepmc.org/article/MED/42938390},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dynamic Changes of Histone H1 Variants in Drug-Induced Senescence.
AU - Nora Mittag
AU - Adriana Birbio
AU - Olga Delipetridou
AU - Pau Homs-Aguadé
AU - Carles Bonet-Costa
AU - Albert Jordan
PY - 2026
DA - 2026/10/14
JO - Genes
DO - 10.3390/genes17101274
UR - https://europepmc.org/article/MED/42938390
AB - Background/Objectives: Cellular senescence is a stress-induced state of irreversible cell cycle arrest triggered by diverse molecular stimuli. It is characterized by distinct phenotypic alterations, including the senescence-associated secretory phenotype (SASP), profound chromatin remodeling, and morphological changes. While senescent cells accumulate during physiological aging, they are also prevalent in pathological contexts such as cancer. Histone H1 is a crucial regulator of chromatin organization and gene expression, and emerging evidence suggests that its content and nuclear distribution change dynamically during senescence. Methods: Here, we investigated the expression and localization dynamics of six somatic H1 variants (H1.0, H1.2 to H1.5, and H1X) upon senescence induction in T47D breast cancer cells, evaluating their correlation with chromatin structural alterations, repetitive element expression, and interferon response activation. Senescence was triggered using doxorubicin, a topoisomerase inhibitor, among other drugs tested, which was confirmed by the accumulation of standard senescence markers (ß-galactosidase activity, p21CIP1/WAF1, H3K9me3, and γH2AX). Results: We observed variant-specific expression patterns, suggesting distinct functional contributions to senescence. Specifically, H1.0 was upregulated, whereas H1.3, H1.4 and H1.5 were downregulated. Furthermore, the nuclear redistribution of H1.2, H1.3, and H1.5 points to their active roles in local gene expression and silencing. These alterations coincided with the increased transcription of repetitive elements (LINEs, SINEs, LTRs and satellites) and the elevated expression of interferon-stimulated genes (IFI27, OASL, IFIT3), likely driven by localized chromatin decompression. Finally, functional knock-down experiments revealed that while the depletion of individual H1 variants yielded distinct cellular effects, it neither sufficed to fully mimic drug-induced senescence nor significantly altered the cellular response to senescence-inducing drugs. Conclusions: Taken together, our findings indicate that while H1 variant deregulation may be a hallmark of senescent breast cancer cells, and linker histones may actively modulate the threshold for senescence induction and genotoxic response, it represents one component of a broader, coordinated chromatin remodeling program.
SN - 2073-4425
ER -