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

View ORCID ProfileBérénice A. Benayoun, Elizabeth A. Pollina, Param Priya Singh, View ORCID ProfileSalah Mahmoudi, View ORCID ProfileItamar Harel, Kerriann M. Casey, Ben W. Dulken, View ORCID ProfileAnshul Kundaje, View ORCID ProfileAnne Brunet
doi: https://doi.org/10.1101/336172
Bérénice A. Benayoun
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
2Current affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
3USC Norris Comprehensive Cancer Center, Los Angeles, CA 90089
4USC Stem Cell Initiative, Los Angeles, CA 90089
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  • For correspondence: berenice.benayoun@usc.edu anne.brunet@stanford.edu
Elizabeth A. Pollina
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
5Harvard Medical School, Boston, MA 02115, USA
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Param Priya Singh
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Salah Mahmoudi
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Itamar Harel
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
6Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, 91904, Israel
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Kerriann M. Casey
7Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
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Ben W. Dulken
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Anshul Kundaje
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Anne Brunet
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
8Paul F. Glenn Laboratories for the Biology of Aging, Stanford University, Stanford, CA 94305, USA
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  • For correspondence: berenice.benayoun@usc.edu anne.brunet@stanford.edu
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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 4 tissues and one cell type from young, middle-age, and old mice, yielding 143 high-quality datasets. We focused specifically 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 datasets from all tissues identified recurrent age-related chromatin and transcriptional changes in key processes, including the upregulation of immune system response pathways such as the interferon signaling pathway. The upregulation of interferon response pathway with age was accompanied by increased transcription of various endogenous retroviral sequences. Pathways deregulated during mouse aging across tissues, notably innate immune pathways, were also deregulated with aging in other vertebrate species – African turquoise killifish, rat, and humans – indicating common signatures of age across species. To date, our dataset represents the largest multi-tissue epigenomic and transcriptomic dataset for vertebrate aging. This resource identifies chromatin and transcriptional states that are characteristic of youthful tissues, which could be leveraged to restore aspects of youthful functionality to old tissues.

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Posted May 31, 2018.
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Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses
Bérénice A. Benayoun, Elizabeth A. Pollina, Param Priya Singh, Salah Mahmoudi, Itamar Harel, Kerriann M. Casey, Ben W. Dulken, Anshul Kundaje, Anne Brunet
bioRxiv 336172; doi: https://doi.org/10.1101/336172
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Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses
Bérénice A. Benayoun, Elizabeth A. Pollina, Param Priya Singh, Salah Mahmoudi, Itamar Harel, Kerriann M. Casey, Ben W. Dulken, Anshul Kundaje, Anne Brunet
bioRxiv 336172; doi: https://doi.org/10.1101/336172

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