Single-cell epigenomics uncovers heterochromatin instability and transcription factor dysfunction during mouse brain aging.
| Title: | Single-cell epigenomics uncovers heterochromatin instability and transcription factor dysfunction during mouse brain aging. |
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| Authors: | Amaral ML; Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA.; Mamde S; Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Miller M; Center for Epigenomics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Hou X; Center for Epigenomics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Arzavala J; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Osteen J; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Johnson ND; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Smoot EW; Center for Epigenomics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Yang Q; Center for Epigenomics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Eisner E; Center for Epigenomics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Zeng Q; Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.; Báez-Becerra CT; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Olness J; Center for Epigenomics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Kern JC; Center for Epigenomics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Rink J; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Barcoma A; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Cho S; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Cao S; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Emerson N; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Lee J; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Willier J; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Loe T; Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Jiao H; Center for Epigenomics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Zu S; Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Zhu Q; Center for Epigenomics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Preissl S; Center for Epigenomics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany; Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria; Field of Excellence BioHealth, University of Graz, Graz, Austria.; Wang A; Center for Epigenomics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.; Ecker JR; Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.; Behrens MM; Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: mbehrens@salk.edu.; Ren B; Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; New York Genome Center, New York, NY 10013, USA; Departments of Genetics and Development, Biochemistry and Molecular Biophysics, and Systems Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: bren@nygenome.org. |
| Source: | Cell reports [Cell Rep] 2026 Mar 24; Vol. 45 (3), pp. 117073. Date of Electronic Publication: 2026 Mar 12. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Cambridge, MA] : Cell Press, c 2012- |
| MeSH Terms: | Heterochromatin*/metabolism ; Heterochromatin*/genetics ; Brain*/metabolism ; Aging*/genetics ; Aging*/metabolism ; Single-Cell Analysis*/methods ; Transcription Factors*/metabolism ; Epigenomics*/methods; Neurons/metabolism ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism ; Animals ; Mice ; Mice, Inbred C57BL ; Male |
| Abstract: | The mechanisms regulating transcriptional changes during brain aging remain poorly understood. Here, we use single-cell epigenomics to profile chromatin accessibility and gene expression across eight mouse brain regions at 2, 9, and 18 months of age. In addition to a marked decline in progenitor populations involved in neurogenesis and myelination, we observe widespread and concordant age-associated changes in transcription and chromatin accessibility across both neuronal and glial cell types. These alterations are accompanied by dysregulation of master transcription factors and a shift toward stress-response programs driven by activator protein 1 (AP-1), indicating progressive drift in cellular identity with aging. We further identify region- and cell-type-specific heterochromatin loss, characterized by increased accessibility at H3K9me3-marked domains, activation of transposable elements, and upregulation of long noncoding RNAs, particularly in glutamatergic neurons. Together, these findings reveal age-related disruption of heterochromatin maintenance and transcriptional regulation, highlighting vulnerable brain regions, cell types, and molecular pathways in brain aging.; (Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of interests J.R.E. is a member of the scientific advisory board for Zymo Research and Ionis. B.R. is a co-founder and consultant of Arima Genomics Inc. and co-founder of Epigenome Technologies. |
| Comments: | Update of: bioRxiv. 2025 May 20:2025.04.21.649585. doi: 10.1101/2025.04.21.649585.. (PMID: 40475496) |
| Grant Information: | R01 AG066018 United States AG NIA NIH HHS |
| Contributed Indexing: | Keywords: CP: genomics; CP: neuroscience; aging; epigenome; heterochromatin; mouse brain; single-cell; transposable elements |
| Substance Nomenclature: | 0 (Heterochromatin); 0 (Transcription Factors); 0 (RNA, Long Noncoding) |
| Entry Date(s): | Date Created: 20260313 Date Completed: 20260327 Latest Revision: 20260521 |
| Update Code: | 20260521 |
| PubMed Central ID: | PMC13189690 |
| DOI: | 10.1016/j.celrep.2026.117073 |
| PMID: | 41824460 |
| Database: | MEDLINE |
Journal Article