Genome-wide transcript and protein analysis reveals distinct features of aging in the mouse heart

Abstract

Understanding the molecular mechanisms underlying age-related changes in the heart is challenging due to the contributions from numerous genetic and environmental factors. Genetically diverse outbred mice provide a model to study the genetic regulation of aging processes in healthy tissues from individuals undergoing natural aging in a controlled environment. We analyzed transcriptome and proteome data from outbred mice at 6, 12 and 18 months of age to reveal a scenario of cardiac hypertrophy, fibrosis, extracellular matrix remodeling, and reemergence of fetal gene expression patterns. We observed widespread changes in protein trafficking and sorting, and post-translational disruption of the stoichiometry of the protein quality control system itself. We identified genome hotspots of age-by-genetic effects that regulate proteins from the proteasome and endoplasmic reticulum stress response, suggesting that genetic variation in these modules may contribute to individual variation in the aging heart.

Genetic dissection of the pluripotent proteome through multi-omics data integration

“…We found many fewer distant pQTL (n = 621) that map outside of the local genomic window. As with previous pQTL studies of similar size in DO mice (Chick et al, 2016;Gyuricza et al, 2022), local pQTL tend to be more significant than distant pQTL (local median LOD = 10.8; distant median LOD = 7.9), and for over 80% of genes that have a local pQTL, we also detected an eQTL for the cognate transcript. For most of these local eQTL-pQTL pairs, the founder strain allele effects at the peak SNP are highly correlated (75% of local pairs are significant at FDR < 0.05; median r = 0.9), consistent with a single causal variant driving both transcript and protein abundance (Fig 4B).…”

“…< 5 x 10 -4 ) (Fig S2C). The molecular basis of these sex differences remains to be established; however, they are also observed in adult mouse liver (Keele et al, 2021) and heart proteomes (Gyuricza et al, 2022), and are therefore unlikely to play a unique role in establishing or maintaining pluripotency.…”

Misexpression of genes lacking CpG islands drives degenerative changes during aging

“…To understand how expression of CGI + and CGI − genes (table S2) changes during aging, we performed RNA sequencing (RNA-seq) of kidneys and hearts from diversity outbred (DO) mice. DO mice are a genetically diverse mouse resource that mimics the complexity of the human population with variable rates of physiological aging ( 12 , 13 ). Figure 1B shows an example of gene expression in kidneys from 18- and 6-month-old mice, where 33.71% of CGI − genes were up-regulated over twofold in the aged kidney compared to the young kidney.…”

“…For DO mice, raw RNA-seq data were aligned as described previously ( 12 , 13 ). Briefly, Genotyping By RNA-Seq software ( https://gbrs.readthedocs.io/en/latest/ ) was used to align RNA-seq reads and to reconstruct the individual haplotypes of DO mice, and total expression levels were measured using Expectation-Maximization algorithm for Allele Specific Expression ( 64 ).…”

“…1C). We then performed the same analysis across 192 kidneys and hearts of DO mice in three chronological age groups (6,12, or 18 months old; n = 64 per group) using the median gene expression in young mice as a reference. The distribution of global gene expression was significantly shifted with age (fig.…”