Which mouse multiparental population is right for your study? The Collaborative Cross inbred strains, their F1 hybrids, or the Diversity Outbred population

G3 Genes Genomes Genetics, Journal Year: 2023, Volume and Issue: 13(4)

Published: Feb. 3, 2023

Multiparental populations (MPPs) encompass greater genetic diversity than traditional experimental crosses of two inbred strains, enabling broader surveys variation underlying complex traits. Two such mouse MPPs are the Collaborative Cross (CC) panel and Diversity Outbred (DO) population, which descended from same eight strains. Additionally, F1 intercrosses CC strains (CC-RIX) have been used enable study designs with replicate outbred mice. Genetic analyses commonly by researchers to investigate traits in these include characterizing how heritable a trait is, i.e. its heritability, mapping loci, quantitative loci (QTLs). Here we evaluate relative merits for tasks through simulation, as well provide recommendations performing analyses. We find that sample animals, possible CC-RIX, more efficient precise estimates heritability. report QTL power curves CC, DO across range effect sizes polygenic backgrounds samples 174 500 The utility animals CC-RIX QTLs rapidly decreased became polygenic. Only large mice were well-powered detect smaller (7.5-10%) highly (80% background). All results generated our R package musppr, developed simulate data user-provided genotypes.

Language: Английский

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Translation is an emerging constraint on protein homeostasis in ageing

Trends in Cell Biology, Journal Year: 2024, Volume and Issue: 34(8), P. 646 - 656

Published: Feb. 28, 2024

Proteins are molecular machines that provide structure and perform vital transport, signalling enzymatic roles. expressed by cells require tight regulation of their concentration, folding, localisation, modifications; however, this state protein homeostasis is continuously perturbed tissue-level stresses. While in healthy tissues able to buffer against these perturbations, for example, expression chaperone proteins, lost ageing, can lead aggregation characteristic folding diseases. Here, we review reports a progressive disconnect between transcriptomic proteomic during cellular ageing. We discuss how age-associated changes responses specific stressors the tissue microenvironment exacerbated loss ribosomal pausing, mistranslation.

Language: Английский

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Methylome–proteome integration after late‐life voluntary exercise training reveals regulation and target information for improved skeletal muscle health

The Journal of Physiology, Journal Year: 2024, Volume and Issue: 603(1), P. 211 - 237

Published: July 26, 2024

Exercise is a potent stimulus for combatting skeletal muscle ageing. To study the effects of exercise on in preclinical setting, we developed combined endurance-resistance training mice called progressive weighted wheel running (PoWeR). PoWeR improves molecular, biochemical, cellular and functional characteristics promotes aspects partial epigenetic reprogramming when performed late life (22-24 months age). In this investigation, leveraged pan-mammalian DNA methylome arrays tandem mass-spectrometry proteomics to provide detailed information late-life adaptations female relative age-matched sedentary controls (n = 7-10 per group). Differential CpG methylation at conserved promoter sites was related transcriptional regulation genes as well Nr4a3, Hes1 Hox after PoWeR. Using holistic method -omics integration binding expression target analysis (BETA), changes were associated with upregulated proteins global mitochondrial translation (P 0.03). Specifically, BETA implicated control ribosomal, mitoribosomal, complex I protein abundance training. may also influence LACTB, MIB1 UBR4 induction - all are mechanistically linked health. Computational cistrome predicted several transcription factors including MYC regulators trained methylome-proteome landscape, corroborating prior transcriptome data. Correlating proteome mass fatigue resistance revealed positive relationships VPS13A NPL levels, respectively. Our findings expose differential proteomic translational that could function aged mice. KEY POINTS: Late-life from 22-24 age shown improve vivo promote mitigation. Integration 36k using (which contain ageing clock sites) exploratory extends our work reveals coordinated widespread initiation, ribosomal (mitoribosomal) voluntary sizeable cohort group analysis). Multi-omics serine β-lactamase-like (LACTB tumour muscle), mind bomb 1 (MIB1 satellite cell type 2 fibre maintenance) ubiquitin ligase E3 component N-recognin 4 (UBR4 quality control) identified regulator proteome, agreement analyses. Vacuolar sorting 13 homolog A (VPS13A) positively correlated mass, glycoprotein/glycolipid sialylation enzyme N-acetylneuraminate pyruvate lyase (NPL) resistance.

Language: Английский

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Genome-wide transcript and protein analysis highlights the role of protein homeostasis in the aging mouse heart

Genome Research, Journal Year: 2022, Volume and Issue: unknown

Published: March 11, 2022

Investigation of the molecular mechanisms aging in human heart is challenging because confounding factors, such as diet and medications, well limited access to tissues from healthy individuals. The laboratory mouse provides an ideal model study individuals a controlled environment. However, previous studies have examined only narrow range genetic variation that shapes individual differences during aging. Here, we analyze transcriptome proteome data 185 genetically diverse male female mice at ages 6, 12, 18 mo characterize changes occur heart. Transcripts proteins reveal activation pathways related exocytosis cellular transport with age, whereas processes involved protein folding decrease age. Additional are apparent including reduced fatty acid oxidation increased autophagy. For form complexes, see decline correlation between their component subunits suggesting age-related loss stoichiometry. most affected complexes themselves homeostasis, which potentially contributes cycle progressive breakdown quality control Our findings highlight important role post-transcriptional regulation In addition, identify loci modulate can alter process.

Language: Английский

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Role of Senescent Cells in Cutaneous Wound Healing

Biology, Journal Year: 2022, Volume and Issue: 11(12), P. 1731 - 1731

Published: Nov. 29, 2022

Cellular senescence has gained increasing attention in the field of aging research. Senescent cells have been implicated biological processes, tumorigenesis, development, and wound repair amongst other processes pathologies. Recent findings reveal that senescent can both promote inhibit cutaneous healing processes. Relating acute chronic wounds will help to clarify their role inform our understanding cell heterogeneity. To this apparent contradiction guide future research therapeutic we review rapidly growing cellular its biology.

Language: Английский

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GLIS1 alleviates cell senescence and renal fibrosis through PGC1-α mediated mitochondrial quality control in kidney aging

Free Radical Biology and Medicine, Journal Year: 2023, Volume and Issue: 209, P. 171 - 184

Published: Oct. 16, 2023

Mitochondrial dysfunction is implied as a crucial factor in age-related chronic kidney disease. It confirmed that Gli-like transcription 1 (GLIS1) involved renal fibrosis, however, the correlation between mitochondrial disturbances and GLIS1-driven aging are not clearly clarified. Thus, we investigated regulatory mechanism of GLIS1 homeostasis quality control both vivo vitro. The lower expression was identified natural accelerated aged models, accompanied by dysfunctions control, including enhanced fission, reduced biogenesis mitophagy, whereas, could maintain stability interacting with peroxisome proliferator-activated receptor γ coactivator-1α (PGC1-α). Additionally, over-expressed inhibited extracellular matrix accumulation alleviated fibrosis while siGLIS1 PGC1-α transcription, well affecting its mitochondria-protective functions. Collectively, demonstrated mediated through targeting aging, which might be promising therapeutic target for attenuating cell senescence fibrosis.

Language: Английский

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Relationships between protein degradation, cellular senescence, and organismal aging

The Journal of Biochemistry, Journal Year: 2024, Volume and Issue: 175(5), P. 473 - 480

Published: Feb. 13, 2024

Abstract Aging is a major risk factor for many diseases. Recent studies have shown that age-related disruption of proteostasis leads to the accumulation abnormal proteins and dysfunction two intracellular proteolytic pathways, ubiquitin-proteasome pathway, autophagy-lysosome largely responsible this process. Conversely, it has been activation these pathways may contribute lifespan extension suppression pathological conditions, making promising intervention anti-aging. This review provides an overview important role protein degradation in aging summarizes how involved

Language: Английский

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A multiomic atlas of the aging hippocampus reveals molecular changes in response to environmental enrichment

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 16, 2024

Abstract Aging involves the deterioration of organismal function, leading to emergence multiple pathologies. Environmental stimuli, including lifestyle, can influence trajectory this process and may be used as tools in pursuit healthy aging. To evaluate role epigenetic mechanisms context, we have generated bulk tissue single cell multi-omic maps male mouse dorsal hippocampus young old animals exposed environmental stimulation form enriched environments. We present a molecular atlas aging process, highlighting two distinct axes, related inflammation dysregulation mRNA metabolism, at functional RNA protein level. Additionally, report alteration heterochromatin domains, loss bivalent chromatin uncovering heterochromatin-switch phenomenon whereby constitutive is partially mitigated through gains facultative heterochromatin. Notably, observed reversal great number aging-associated alterations context enrichment, which was particularly linked glial oligodendrocyte pathways. In conclusion, our work describes epigenomic landscape reveals how lifestyle intervention lead multi-layered decline.

Language: Английский

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Positive and negative feedback regulation of the TGF-β1 explains two equilibrium states in skin aging

iScience, Journal Year: 2024, Volume and Issue: 27(5), P. 109708 - 109708

Published: April 10, 2024

Language: Английский

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Statistically and functionally fine-mapped blood eQTLs and pQTLs from 1,405 humans reveal distinct regulation patterns and disease relevance

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(10), P. 2054 - 2067

Published: Sept. 24, 2024

Studying the genetic regulation of protein expression (through quantitative trait loci (pQTLs)) offers a deeper understanding regulatory variants uncharacterized by mRNA (expression QTLs (eQTLs)) studies. Here we report cis-eQTL and cis-pQTL statistical fine-mapping from 1,405 genotyped samples with blood 2,932 plasma expression, as part Japan COVID-19 Task Force (JCTF). Fine-mapped eQTLs (n = 3,464) were enriched for 932 validated massively parallel reporter assay. pQTLs 582) missense variations on structured extracellular domains, although possibility epitope-binding artifacts remains. Trans-eQTL trans-pQTL analysis highlighted associations class I HLA allele variation KIR genes. We contrast multi-tissue origin mRNA, contributing to limited colocalization level, distinct mechanisms relevance pQTLs. negative correlation between ABO because linkage disequilibrium nearby

Language: Английский

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