Tissue-specific responses to DNA damage limit function and regulate ageing in progeroid mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA852169 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19795628_1.fastq.gz | Fastqsanger.gz | |||
| SRR19795628_2.fastq.gz | Fastqsanger.gz | |||
| SRR19795629_1.fastq.gz | Fastqsanger.gz | |||
| SRR19795629_2.fastq.gz | Fastqsanger.gz | |||
| SRR19795630_1.fastq.gz | Fastqsanger.gz |
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Project description:DNA repair deficiency can lead to segmental phenotypes in humans and mice, in which certain tissues lose homeostasis while others remain seemingly unaffected. This may be due to different tissues facing varying levels of damage or having different reliance on specific DNA repair pathways. However, we find that the cellular response to DNA damage determines different tissue-specific outcomes. Here, we use a mouse model of the human XPF-ERCC1 progeroid syndrome (XFE) caused by loss of DNA repair. We find that p53, a central regulator of the cellular response to DNA damage, regulates tissue dysfunction in Ercc1-/- mice in different ways. We show that ablation of p53 rescues the loss of hematopoietic stem cells, and has no effect on kidney, germ cell or brain dysfunction, but exacerbates liver pathology and polyploidisation. Mechanistically, we find that p53 ablation led to the loss of cell-cycle regulation in the liver, with reduced p21 expression. Eventually, p16/Cdkn2a expression is induced, serving as a fail-safe brake to proliferation in the absence of the p53-p21 axis. Taken together, our data show that distinct and tissue-specific functions of p53, in response to DNA damage, play a crucial role in regulating tissue-specific phenotypes.
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Project description:Dietary composition can significantly influence health and lifespan, however, robust knowledge on which food components, at what concentration exert which long-term health effects is still incomplete. Here, we explored the effects of dietary protein intake on Ercc1Δ/- DNA-repair-deficient mice, which are an excellent model for accelerated ageing and are hyperresponsive to the anti-ageing effect of dietary restriction. Restricting dietary protein by 50% extended lifespan in male mice, but not in females. Restricting protein levels beyond 80% improved various neurological health parameters, while a further reduction to 95% affected appetite and became distinctly detrimental. Conversely, a near doubling of protein intake and isocaloric compensatory lowering with carbohydrates significantly shortened lifespan in both sexes. Gene expression analysis of liver from mice on a high-protein, low-carbohydrate diet to those on high-carbohydrate, low-protein revealed increased expression of oxidative phosphorylation, enrichment of processes associated with tissue injury, inflammation, and gene-length-dependent transcriptional decline (GLTD), recently shown to be indicative of DNA damage accumulation causing transcription stress, and cellular ageing. Finally, GLTD was also identified by reanalysis of publicly available data of wild-type mice, rats and humans on high-protein diets, suggesting that increased dietary protein enhances GLTD and accelerates systemic ageing. Together, our findings have implications for nutritional guidelines for progeroid DNA-repair-deficient human syndromes, caution against excessive protein intake in the context of sustaining health, and suggest GLTD as a sensitive read-out of overall health and a predictor of biological ageing.
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Project description:Progeroid syndromes are rare genetic diseases with a majority of autosomal dominant transmission, the prevalence of which is less than 1 / 10,000,000. These syndromes caused by mutations in the LMNA gene encoding A-type Lamins belong to the group of disorders called laminopathies. Lamins are implicated in the architecture and function of the nucleus and chromatin. Patients affected with progeroid laminopathies display accelerated ageing of mesenchymal stem cells (MSCs)-derived tissues associated with nuclear morphological abnormalities. In order to identify pathways altered in progeroid patients’ MSCs, we used induced pluripotent stem cells (hiPSCs) from patients affected with classical Hutchinson-Gilford Progeria Syndrome (HGPS, c.1824C>T - p.G608G), HGPS-Like Syndrome (HGPS-L; c.1868C>G - p.T623S) associated with farnesylated prelamin A accumulation, or Atypical Progeroid Syndromes (APS; homozygous c.1583C> T - p.T528M; heterozygous c.1762T>C - p.C588R; compound heterozygous c.1583C>T and c.1619T>C - p.T528M and p.M540T) without progerin accumulation. By comparative analysis of the transcriptome and methylome of hiPSC-derived MSCs, we found that patient’s MSCs display specific DNA methylation patterns and modulated transcription at early stages of differentiation. We further explored selected biological processes deregulated in the presence of LMNA variants and confirmed alterations of age-related pathways during MSC differentiation. In particular, we report the presence of an altered mitochondrial pattern, an increased response to double-strand DNA damage and telomere erosion in HGPS, HGPS-L and APS MSCs, suggesting converging pathways, independent of progerin accumulation, but a distinct DNA methylation profile in HGPS and HGPS-L compared to APS cells.
2022-09-12 | GSE202368 | GEO
Project description:Progeroid syndromes are rare genetic diseases with a majority of autosomal dominant transmission, the prevalence of which is less than 1 / 10,000,000. These syndromes caused by mutations in the LMNA gene encoding A-type Lamins belong to the group of disorders called laminopathies. Lamins are implicated in the architecture and function of the nucleus and chromatin. Patients affected with progeroid laminopathies display accelerated ageing of mesenchymal stem cells (MSCs)-derived tissues associated with nuclear morphological abnormalities. In order to identify pathways altered in progeroid patients’ MSCs, we used induced pluripotent stem cells (hiPSCs) from patients affected with classical Hutchinson-Gilford Progeria Syndrome (HGPS, c.1824C>T - p.G608G), HGPS-Like Syndrome (HGPS-L; c.1868C>G - p.T623S) associated with farnesylated prelamin A accumulation, or Atypical Progeroid Syndromes (APS; homozygous c.1583C> T - p.T528M; heterozygous c.1762T>C - p.C588R; compound heterozygous c.1583C>T and c.1619T>C - p.T528M and p.M540T) without progerin accumulation. By comparative analysis of the transcriptome and methylome of hiPSC-derived MSCs, we found that patient’s MSCs display specific DNA methylation patterns and modulated transcription at early stages of differentiation. We further explored selected biological processes deregulated in the presence of LMNA variants and confirmed alterations of age-related pathways during MSC differentiation. In particular, we report the presence of an altered mitochondrial pattern, an increased response to double-strand DNA damage and telomere erosion in HGPS, HGPS-L and APS MSCs, suggesting converging pathways, independent of progerin accumulation, but a distinct DNA methylation profile in HGPS and HGPS-L compared to APS cells.
2022-09-12 | GSE202364 | GEO
Project description:Ageing is a complex multifactorial process, impacting all organs and tissues, with DNA damage accumulation serving as a common underlying cause. To decelerate ageing, various strategies have been applied to model organisms and evaluated for health and lifespan benefits. Dietary restriction (DR, also known as caloric restriction) is a well-established long-term intervention recognised for its universal anti-ageing effects. DR temporarily suppresses growth, and when applied to progeroid DNA repair-deficient mice doubles lifespan with systemic health benefits. Counterintuitively, attenuation of myostatin/activin signalling by soluble activin receptor (sActRIIB), boosts the growth of muscle, and in these animals prevents muscle wasting, improves kidney functioning, and compresses morbidity. Here we investigated a combined approach, applying an anabolic regime (sActRIIB) at the same time as DR to Ercc1d/- progeroid mice. Following both single treatments and combined, we monitored global effects on body weight, lifespan and behaviour, and local effects on muscle and tissue weight, muscle morphology and function, and ultrastructural and transcriptomic changes in muscle and kidney. Lifespan was mostly influenced by DR (extended from approx. 20 to 40-weeks; p<0.001), with sActRIIB clearly increasing muscle mass (35-65%) and tetanic force (p<0.001). The combined regime yielded a stable uniform body weight, but increased compared to DR alone, synergistically improved motor coordination and further delayed the onset and development of balance problems. sActRIIB significantly increased muscle fibre size (p<0.05) in mice subjected to DR and lowered all signs of muscle damage. In the neuromuscular junction of Ercc1d/- mice the junctional folding of the basement membrane at the postsynaptic side was either rudimentary or completely missing. Single interventions by sActRIIB treatment or DR only partially rescued this phenotype, while in the double intervention group the regularly shaped junctional foldings were maintained. In kidney of Ercc1d/- mice we observed a mild but significant foot process effacement, which was restored by either intervention. Transcriptome analysis also pointed towards reduced levels of DNA damage in muscle and kidney by DR, but not sActRIIB, while these levels retained lower in the double intervention. In muscle we found synergistic effects of combining sActRIIB with DR, but not in kidney, with an overall better health in the double intervention group. Crucially, the benefits of each single intervention are not lost when administered in combination, but rather strengthened, even when sActRIIB was applied late in life, opening opportunities for translation to human.
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Project description:ERCC1 is a DNA endonuclease participating in the Nucleotide Excision Repair (NER) pathway. Its functionality is related to XPF; the two proteins work as a heterodimer to incise the 5 of a 30-mer that contains the damaged nucleotide and remove the fragment together with XPG. Apart from NER deficiency, mutated Ercc1 in mice and humans causes a series of progeroid symptoms (premature ageing). We hypothesize that there are undescribed functions of ERCC1, possibly in transcriptional regulation that contribute to the development of the striking phenotypes observed. The aim is to identify previously uncharacterized protein partners of ERCC1 that might contribute to our understanding of its differential roles during DNA damage-driven progeria.
2023-10-04 | PXD017063 | Pride
Project description:Progeroid syndromes are rare genetic disorders that phenotypically resemble natural aging. Despite identification of causal mutations, mechanisms that generate their clinical manifestations remain elusive. Here, we identified a DNA replication timing (RT) signature that distinguishes progeroid syndromes from normal aging and identifies TP63 gene as a new disease marker. Abnormal TP63 RT appears early during differentiation of progeroid iPSCs and is associated with altered gene variant expression. Our findings demonstrate the utility of RT signatures to identify novel biomarkers not detected by other methods, reveal abnormal TP63 RT as an early event in progeroid disease progression and offer TP63 gene regulation as a potential therapeutic target.
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