TY - JOUR
T1 - Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses
AU - Benayoun, Bérénice A.
AU - Pollina, Elizabeth A.
AU - Singh, Param Priya
AU - Mahmoudi, Salah
AU - Harel, Itamar
AU - Casey, Kerriann M.
AU - Dulken, Ben W.
AU - Kundaje, Anshul
AU - Brunet, Anne
N1 - Funding Information: We thank Aaron Newman and Ash Alizadeh for advice on the use of CIBERSORT for RNA-seq de-convolution and Art Owen for advice on statistical analyses. We thank Ashley Webb for assistance in tissue dissection for ChIP-seq and RNA-seq and Katja Hebestreit for advice on ChIP-seq and RNA-seq analyses. We thank Lauren Booth, Kévin Contrepois, Aaron Daugherty, C. David Lee, Dena Leeman, John Tower, Marc Vermulst, and Robin Yeo for feedback on analyses and manuscript. We thank Matthew Buckley, Brittany Demmitt, Andrew McKay, and Robin Yeo for independent code-checking. Illumina HiSeq 2000 sequencing was performed at the Stanford Genome Sequencing Service Center, and Illumina NextSeq 500 sequencing was performed at the Stanford Functional Genomics Facility, supported in part by National Institutes of Health (NIH) P30 CA124435 through the use of the Genetics Bioinformatics Service Center (Stanford Cancer Institute Shared Resource). Support for this work was provided by NIH DP1 AG044848 (A.B.), NIH P01 AG036695 (A.B. and A.K.), a generous gift from Tim and Michele Barakett (A.B.), NIH R00 AG049934 (B.A.B.), the Hanson-Thorell family fellowship (B.A.B.), and NIH F31 AG043232 (E.A.P.). Publisher Copyright: © 2019 Benayoun et al.
PY - 2019/4
Y1 - 2019/4
N2 - 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 age-related 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.
AB - 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 age-related 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.
UR - http://www.scopus.com/inward/record.url?scp=85064050921&partnerID=8YFLogxK
U2 - https://doi.org/10.1101/gr.240093.118
DO - https://doi.org/10.1101/gr.240093.118
M3 - Article
C2 - 30858345
SN - 1088-9051
VL - 29
SP - 697
EP - 709
JO - Genome Research
JF - Genome Research
IS - 4
ER -