Inflammation-induced epigenetic erosion drives stem cell ferroptosis during aging (PRO-Seq)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA944712 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23865828_1.fastq.gz | Fastqsanger.gz | |||
| SRR23865828_2.fastq.gz | Fastqsanger.gz | |||
| SRR23865829_1.fastq.gz | Fastqsanger.gz | |||
| SRR23865829_2.fastq.gz | Fastqsanger.gz | |||
| SRR23865830_1.fastq.gz | Fastqsanger.gz |
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Project description:Aging is a complex process associated with multiple events that lead to the decline in stem cell number and function. However, the relationship between these events and their initiation in biological systems remains ambiguous. Here, we investigate the effects of sustained, low-grade systemic inflammation on muscle stem cells (MuSCs) during aging. We show that the slow rise in inflammation during aging causes long-lasting epigenetic remodeling in MuSCs, leading to premature exit of quiescence followed by rapid ferroptotic cell death. The elevation of circulating cytokines results in erosion of histone H4 lysine 20 methylation, fine-tuning of the MuSC transcriptome for future injury response that resembles the Galert state. Prolonged exposure to inflammatory signals during aging results in the loss of H4K20me1 maintenance by lysine methyltransferase 5a (Kmt5a), leading to a disruption of key transcriptional programs required to preserve MuSC quiescence and survival. Mechanistically, we established that Kmt5a genetic deletion prematurely activates MuSC through Notch signaling. Activated cells cannot cycle properly as they display aberrant iron metabolism and repressed Gpx4, resulting in the accumulation of reactive oxygen species, genomic instability, lipid peroxidation, and ultimately, cell death by ferroptosis. Notably, a lifelong reduction in inflammation restores the MuSC number and function and rejuvenates MuSC iron homeostasis. Our findings demonstrates that chronic systemic inflammatory signals reprogram the MuSC epigenome into a primed state, which drives premature cell cycle re-entry and ferroptosis during aging.
2025-04-21 | GSE227366 | GEO
Project description:Aging is a complex process associated with multiple events that lead to the decline in stem cell number and function. However, the relationship between these events and their initiation in biological systems remains ambiguous. Here, we investigate the effects of sustained, low-grade systemic inflammation on muscle stem cells (MuSCs) during aging. We show that the slow rise in inflammation during aging causes long-lasting epigenetic remodeling in MuSCs, leading to premature exit of quiescence followed by rapid ferroptotic cell death. The elevation of circulating cytokines results in erosion of histone H4 lysine 20 methylation, fine-tuning of the MuSC transcriptome for future injury response that resembles the Galert state. Prolonged exposure to inflammatory signals during aging results in the loss of H4K20me1 maintenance by lysine methyltransferase 5a (Kmt5a), leading to a disruption of key transcriptional programs required to preserve MuSC quiescence and survival. Mechanistically, we established that Kmt5a genetic deletion prematurely activates MuSC through Notch signaling. Activated cells cannot cycle properly as they display aberrant iron metabolism and repressed Gpx4, resulting in the accumulation of reactive oxygen species, genomic instability, lipid peroxidation, and ultimately, cell death by ferroptosis. Notably, a lifelong reduction in inflammation restores the MuSC number and function and rejuvenates MuSC iron homeostasis. Our findings demonstrates that chronic systemic inflammatory signals reprogram the MuSC epigenome into a primed state, which drives premature cell cycle re-entry and ferroptosis during aging.
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Project description:Inflammation-induced epigenetic erosion drives stem cell ferroptosis during aging
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Project description:Aging is a complex process associated with multiple events that lead to the decline in stem cell number and function. However, the relationship between these events and their initiation in biological systems remains ambiguous. Here, we investigate the effects of sustained, low-grade systemic inflammation on muscle stem cells (MuSCs) during aging. We show that the slow rise in inflammation during aging causes long-lasting epigenetic remodeling in MuSCs, leading to premature exit of quiescence followed by rapid ferroptotic cell death. The elevation of circulating cytokines results in erosion of histone H4 lysine 20 methylation, fine-tuning of the MuSC transcriptome for future injury response that resembles the Galert state. Prolonged exposure to inflammatory signals during aging results in the loss of H4K20me1 maintenance by lysine methyltransferase 5a (Kmt5a), leading to a disruption of key transcriptional programs required to preserve MuSC quiescence and survival. Mechanistically, we established that Kmt5a genetic deletion prematurely activates MuSC through Notch signaling. Activated cells cannot cycle properly as they display aberrant iron metabolism and repressed Gpx4, resulting in the accumulation of reactive oxygen species, genomic instability, lipid peroxidation, and ultimately, cell death by ferroptosis. Notably, a lifelong reduction in inflammation restores the MuSC number and function and rejuvenates MuSC iron homeostasis. Our findings demonstrates that chronic systemic inflammatory signals reprogram the MuSC epigenome into a primed state, which drives premature cell cycle re-entry and ferroptosis during aging.
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Project description:Aging is a complex process associated with multiple events that lead to the decline in stem cell number and function. However, the relationship between these events and their initiation in biological systems remains ambiguous. Here, we investigate the effects of sustained, low-grade systemic inflammation on muscle stem cells (MuSCs) during aging. We show that the slow rise in inflammation during aging causes long-lasting epigenetic remodeling in MuSCs, leading to premature exit of quiescence followed by rapid ferroptotic cell death. The elevation of circulating cytokines results in erosion of histone H4 lysine 20 methylation, fine-tuning of the MuSC transcriptome for future injury response that resembles the Galert state. Prolonged exposure to inflammatory signals during aging results in the loss of H4K20me1 maintenance by lysine methyltransferase 5a (Kmt5a), leading to a disruption of key transcriptional programs required to preserve MuSC quiescence and survival. Mechanistically, we established that Kmt5a genetic deletion prematurely activates MuSC through Notch signaling. Activated cells cannot cycle properly as they display aberrant iron metabolism and repressed Gpx4, resulting in the accumulation of reactive oxygen species, genomic instability, lipid peroxidation, and ultimately, cell death by ferroptosis. Notably, a lifelong reduction in inflammation restores the MuSC number and function and rejuvenates MuSC iron homeostasis. Our findings demonstrates that chronic systemic inflammatory signals reprogram the MuSC epigenome into a primed state, which drives premature cell cycle re-entry and ferroptosis during aging.
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Project description:Inflammation-induced epigenetic erosion drives stem cell ferroptosis during aging (CUT&Tag)
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Project description:Inflammation-induced epigenetic erosion drives stem cell ferroptosis during aging [scRNA-seq]
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Project description:Hematopoietic aging is defined by a loss of regenerative capacity and skewed differentiation from hematopoietic stem cells (HSC) leading to dysfunctional blood production. Signals from the bone marrow (BM) microenvironment dynamically tailor hematopoiesis, but the effect of aging on the niche and the contribution of the aging niche to blood aging still remains unclear. Here, we show the development of an inflammatory milieu in the aged marrow cavity, which drives both niche and hematopoietic system remodeling. We find decreased numbers and functionality of osteogenic endosteal mesenchymal stromal cells (MSC), expansion of pro-inflammatory perisinusoidal MSCs, and deterioration of the central marrow sinusoidal endothelium, which together create a self-reinforcing inflamed BM milieu. Single cell molecular mapping of old niche cells further confirms disruption of cell identities and enrichment of inflammatory response genes. Inflammation, in turn, drives chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors, which promotes myeloid differentiation at the expense of lymphoid and erythroid commitment, and hinders hematopoietic regeneration. Remarkably, both defective hematopoietic regeneration, niche deterioration and HSC aging can be improved by blocking inflammatory IL-1 signaling. Our results indicate that targeting the pro-inflammatory niche milieu can be instrumental in restoring blood production during aging.
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Project description:Ferroptosis is an iron-dependent form of cell death driven by biochemical and metabolic alterations resulting in oxidation within the lipid compartment. Calcium is a potent signaling molecule ascribed to diverse cellular processes including migration, neurotransmitter function, and cell death. Here we elucidate a crucial link between calcium homeostasis and ferroptotic cell death through the identification of the tetraspanin MS4A15. Ectopic MS4A15 expression specifically protects against ferroptosis by depleting endoplasmic reticulum stores. In an unexpected connection, prolonged calcium dysregulation stimulates fundamental remodeling to ferroptosis-resistant monounsaturated and plasmalogen lipid species. Application of this discovery revealed that augmenting luminal calcium sensitizes cancer cell lines previously refractory to ferroptosis. This finding provides a unique mechanistic basis for ferroptosis sensitivity and resolves a long-standing query into the role of calcium in oxidative cell death. Manipulating calcium homeostasis offers an unprecedented strategy for overcoming therapy resistance in cancer.
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