Coordination in the unfolded protein response during aging in outbred deer mice

Soltanmohammadi, Elham; Farmaki, Elena; Zhang, Youwen; Naderi, Asieh; Kaza, Vimala; Chatzistamou, Ioulia; Kiaris, Hippokratis

doi:10.1016/j.exger.2020.111191

Cited by 10 publications

(7 citation statements)

References 24 publications

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“…To that end, high altitude deer mice may have engaged epigenetic strategies to counteract such immune system suppression. Of note is also the unique methylation profile of P. maniculatus in comparison with P. leucopus that corroborate the recently reported deregulation of stress response genes and the aberrant histological manifestations recorded in aged P. maniculatus 16 . Finally, of interest are the findings related to monogamy that identified high differences in overall baseline methylation between monogamous and polygamous species and a series of genes that are specifically methylated differentially between these groups, irrespectively of the species.…”

Section: Discussionsupporting

confidence: 85%

“…Among them P. leucopus lives up to 8 years in captivity as compared to other Peromyscus species such as P. maniculatus that reportedly have a lifespan of about 4 years 15 . Comparison of brain specimens between older P. leucopus and P. maniculatus indicated that in the latter, coordination of the unfolded protein response is compromised, and evidence of neurodegenerative pathology was obtained 16 .Therefore, comparative analysis of Peromyscus species may be relevant to the study of age-related alterations in the brain. Here, we compared DNAm profile of the P. maniculatus brain to P. leucopus and recorded notable differences.…”

Section: Resultsmentioning

confidence: 99%

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Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy

Horvath

Haghani

Zoller

et al. 2021

Preprint

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DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how stress factors impact aging. Deer mice (Peromyscus) are long living rodents that have emerged as an informative model to study aging, adaptation at extreme environments, and monogamous behavior. In the present study we have undertaken an exhaustive, genome-wide analysis of DNA methylation in Peromyscus, spanning different species, stocks, sexes, tissues and age cohorts. We describe DNA methylation-based estimators of age for different species of deer mice based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for deer mice was trained on 3 tissue sources (tail, liver, brain). Two dual species human-peromyscus clocks accurately measure age and relative age defined as the ratio of chronological age to maximum age. These analyses also allowed us to accurately manifest the increasing impact of age, sex, genetic relatedness, and ultimately tissue identity, in that order, in the acquisition of specific methylation patterns in the genome. Genes that were differentially methylated across different biological variables were determined and their potential impact is discussed. This study describes highly accurate DNA methylation-based estimators of age in deer mice and illustrates how differential methylation may be linked to adaptation at different conditions.

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Section: Discussionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy

Horvath

Haghani

Zoller

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…To that end, high-altitude deer mice may have engaged epigenetic strategies to counteract such immune system suppression which has been linked, among others, to hypoxia at high elevations 27 . Of note is also the unique methylation profile of P. maniculatus in comparison with P. leucopus that corroborate the recently reported deregulation of stress response genes and the aberrant histological manifestations recorded in aged P. maniculatus [26].…”

Section: Discussionsupporting

confidence: 85%

“…Comparison of brain specimens between older P. leucopus and P. maniculatus indicated that in the latter, coordination of the unfolded protein response is compromised, and evidence of neurodegenerative pathology was obtained [ 26 ]. Therefore, comparative analysis of Peromyscus species may be relevant to the study of age-related alterations in the brain.…”

Section: Resultsmentioning

confidence: 99%

Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy

et al. 2021

View full text Add to dashboard Cite

DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how stress factors impact aging. Deer mice (Peromyscus) are long-living rodents that have emerged as an informative model to study aging, adaptation to extreme environments, and monogamous behavior. In the present study, we have undertaken an exhaustive, genome-wide analysis of DNA methylation in Peromyscus, spanning different species, stocks, sexes, tissues, and age cohorts. We describe DNA methylation-based estimators of age for different species of deer mice based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for deer mice was trained on 3 tissues (tail, liver, and brain). Two human-Peromyscus clocks accurately measure age and relative age, respectively. We present CpGs and enriched pathways that relate to different conditions such as chronological age, high altitude, and monogamous behavior. Overall, this study provides a first step towards studying the epigenetic correlates of monogamous behavior and adaptation to high altitude in Peromyscus. The human-Peromyscus epigenetic clocks are expected to provide a significant boost to the attractiveness of Peromyscus as a biological model.

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“…For example, in people suffering from frailty syndrome, this approach readily manifested the involvement of the immune system [ 10 ]. In brain samples of different species of deer mice, it pointed to a loss of smell at aging and identified transcriptomic coordination differences that accompany the development of histological changes consistent with neurodegeneration [ 11 ]. In analyses of liver samples from deer mice receiving a high‐fat diet, this strategy demonstrated the engagement of the immune system, prior to the development of histologically detectable inflammation [ 12 ].…”

mentioning

confidence: 99%

RASSF1 is identified by transcriptome coordination analysis as a target of ATF4

et al. 2023

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Evaluation of gene co‐regulation is a powerful approach for revealing regulatory associations between genes and predicting biological function, especially in genetically diverse samples. Here, we applied this strategy to identify transcripts that are co‐regulated with unfolded protein response (UPR) genes in cultured fibroblasts from outbred deer mice. Our analyses showed that the transcriptome associated with RASSF1, a tumor suppressor involved in cell cycle regulation and not previously linked to UPR, is highly correlated with the transcriptome of several UPR‐related genes, such as BiP/GRP78, DNAJB9, GRP94, ATF4, DNAJC3, and CHOP/DDIT3. Conversely, gene ontology analyses for genes co‐regulated with RASSF1 predicted a previously unreported involvement in UPR‐associated apoptosis. Bioinformatic analyses indicated the presence of ATF4‐binding sites in the RASSF1 promoter, which were shown to be operational using chromatin immunoprecipitation. Reporter assays revealed that the RASSF1 promoter is responsive to ATF4, while ablation of RASSF1 mitigated the expression of the ATF4 effector BBC3 and abrogated tunicamycin‐induced apoptosis. Collectively, these results implicate RASSF1 in the regulation of endoplasmic reticulum stress‐associated apoptosis downstream of ATF4. They also illustrate the power of gene coordination analysis in predicting biological functions and revealing regulatory associations between genes.

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Coordination in the unfolded protein response during aging in outbred deer mice

Cited by 10 publications

References 24 publications

Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy

Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy

Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy

RASSF1 is identified by transcriptome coordination analysis as a target of ATF4

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