Naderi, A. | bioRxiv Science

bioRxiv2023

Variations in cellular unfolded protein response, respiratory capacity, and stress tolerance in skin and lung fibroblasts of deer mice (Peromyscus maniculatus)

Evolutionary physiologists have long been interested in physiological mechanisms underpinning variation in life-history performance. Recent efforts to elucidate these mechanisms focused on bioenergetics and oxidative stress. One underappreciated area that could play a role in mediating variation in performance is the unfolded protein response (UPR), a cellular stress response that reduces secretory protein load, enhances endoplasmic reticulum (ER) protein folding and clearance capacity during stress and during its adaptive phase. Given that the ER and mitochondria interact to regulate cellular homeostasis, it seems intuitive that UPR phenotype would correlate strongly with mitochondrial physiology, which in turn would contribute to variations in whole-organism metabolism. One way researchers have been studying cellular controls of life-history traits is by assessing stress resistance and bioenergetic properties of primary dermal fibroblasts. However, it is unclear if findings from dermal fibroblasts can be generalized to other cell and tissue types, and if fibroblasts phenotypes are repeatable across different life-history stages. This study aimed to explore the relationships between UPR profile, cellular respiration, and stress resistance using primary dermal fibroblasts isolated at puberty and primary lung fibroblasts isolated at adulthood. Specifically, we tested if 1) UPR profile of dermal fibroblasts isolated at puberty corresponds to UPR profile of lung fibroblasts isolated at adulthood, 2) UPR profile of dermal fibroblasts isolated at puberty and lung fibroblasts isolated at adulthood correspond to cellular bioenergetics of lung fibroblasts isolated at adulthood, and 3) UPR profile of dermal fibroblasts isolated at puberty corresponds to multiplex stress resistance (ER stress, oxidative stress, DNA damage) of lung fibroblasts isolated at adulthood. We found that only tunicamycin induced BiP expression was repeatable in skin and lung fibroblasts. Tunicamycin induced expressions of BiP, GRP94, and CNX in skin fibroblasts predicted resistance of lung fibroblasts to tunicamycin, (but not thapsigargin and other inducers of lethal stress), which is indicative for the pro-survival role of UPR during stress. Tunicamycin induced BiP expression in skin and lung fibroblasts also predicted multiple cellular bioenergetics parameters in lung fibroblasts. Statements and DeclarationsNo competing interests declared. This work was supported by National Science Foundation grants IOS1453784 and OIA1736150 to W.R.H., IOS1755670 to the PGSC, and a National Science Foundation EPSCoR pilot grant to K.N.Y. The funders did not have any input into the content of the manuscript nor require approval prior to submission.

physiology↗

bioRxiv2021

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

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.

developmental biology↗

bioRxiv2021

DNA Methylation Networks Underlying Mammalian Traits

Epigenetics has hitherto been studied and understood largely at the level of individual organisms. Here, we report a multi-faceted investigation of DNA methylation across 11,117 samples from 176 different species. We performed an unbiased clustering of individual cytosines into 55 modules and identified 31 modules related to primary traits including age, species lifespan, sex, adult species weight, tissue type and phylogenetic order. Analysis of the correlation between DNA methylation and species allowed us to construct phyloepigenetic trees for different tissues that parallel the phylogenetic tree. In addition, while some stable cytosines reflect phylogenetic signatures, others relate to age and lifespan, and in many cases responding to anti-aging interventions in mice such as caloric restriction and ablation of growth hormone receptors. Insights uncovered by this investigation have important implications for our understanding of the role of epigenetics in mammalian evolution, aging and lifespan.

evolutionary biology↗