Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses

Abstract

Aging is accompanied by the functional decline of tissues. However, a systematic study of epigenomic and transcriptomic changes across tissues during aging is missing. Here, we generated chromatin maps and transcriptomes from four tissues and one cell type from young, middle-aged, and old mice-yielding 143 high-quality data sets. We focused on chromatin marks linked to gene expression regulation and cell identity: histone H3 trimethylation at lysine 4 (H3K4me3), a mark enriched at promoters, and histone H3 acetylation at lysine 27 (H3K27ac), a mark enriched at active enhancers. Epigenomic and transcriptomic landscapes could easily distinguish between ages, and machine-learning analysis showed that specific epigenomic states could predict transcriptional changes during aging. Analysis of data sets from all tissues identified recurrent agerelated chromatin and transcriptional changes in key processes, including the up-regulation of immune system response pathways such as the interferon response. The up-regulation of the interferon response pathway with age was accompanied by increased transcription and chromatin remodeling at specific endogenous retroviral sequences. Pathways misregulated during mouse aging across tissues, notably innate immune pathways, were also misregulated with aging in other vertebrate species-African turquoise killifish, rat, and humans-indicating common signatures of age across species. To date, our data set represents the largest multitissue epigenomic and transcriptomic data set for vertebrate aging. This resource identifies chromatin and transcriptional states that are characteristic of young tissues, which could be leveraged to restore aspects of youthful functionality to old tissues.

Remodeling of the H3 nucleosomal landscape during mouse aging

“…heart, liver, cerebellum, olfactory bulb) and one primary cell type (i.e. primary neural stem cell cultures [NSCs]) at 3 ages throughout mouse lifespan (3, 12 and 29 months of age [22]. Although we do not find evidence for large changes in histone H3 expression levels or nucleosome occupancy across ages, we do identify reproducibly remodeled nucleosomes with mouse aging.…”

Decoding the transcriptional response to ischemic stroke in young and aged mouse brain

“…First, we analyzed factors that may sensitize aged brain to greater stroke damage during normal aging process. A number of studies has documented that inflammation is increased in the aged brain [105][106][107] , and it has been reported that the changes occur predominantly in glial cells 108,109 . Our results are well in line with these reports as we detected upregulation of a number of pro-inflammatory genes (Figures 1A, S1A) that map to signatures of aged and reactive glial cells, including the signature of a recently identified subpopulation of Ccl4+ pro-inflammatory microglia 60,61 (Figures 1B, S2).…”

Transcriptome analysis reveals the difference between “healthy” and “common” aging and their connection with age‐related diseases

“…Gene expression and other types of “omics” data have been widely used to study the process of aging (Edwards et al, ; Peters et al, ). For examples, epigenome and transcriptome landscapes with aging in mice have revealed widespread induction of inflammatory responses (Benayoun et al, ); likewise, the downregulation of mitochondrial genes across human tissues has been consistently reported (Glass et al, ; Yang et al, ). Studying transcriptomes across multiple species with varied lifespans has similarly reveled a potential role for gene expression regulation in contributing to longer lifespans (S. Ma et al, ).…”