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Peer-reviewedCC BYScience

Epigenetic and 3D genome reprogramming during the aging of the human hippocampus

  • Nathan R. Zemke1,2,3
  • Seo Yeon Lee2,3
  • Sainath Mamde2,3
  • Bing Yang1,2,3
  • Nicole C. Berchtold4,5,6
  • B. Maximiliano Garduño4,6
  • Hannah S. Indralingam1,2,3
  • Weronika M. Bartosik1,2,3
  • Pik Ki Lau1,2,3
  • Keyi Dong1,2,3
  • Emily Hsu1,7,3
  • Amanda Yang2,3
14 more authors
  • Yasmine Tani2,3
  • Chumo Chen2,3
  • Qiurui Zeng2,6
  • Varun Ajith4,6
  • Liqi Tong4,8
  • Chanrung Seng9,8
  • Daofeng Li9,8
  • Ting Wang9,10,6
  • Jingtian Zhou11,12,13
  • Joseph R. Ecker12,14
  • Christopher K. Glass2,15
  • Carl W. Cotman16,17
  • Xiangmin Xu4,18
  • Bing Ren2,19,20
20 affiliations
  1. 1Center for Epigenomics, University of California, San Diego School of Medicine, La Jolla, CA, USA
  2. 2Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA
  3. 3University of California, San Diego
  4. 4Department of Anatomy and Neurobiology, University of California, Irvine School of Medicine, Irvine, CA, USA
  5. 5Immunis Inc., Irvine, CA, USA
  6. 6University of California, Irvine
  7. 7Department of Biochemistry and Molecular Medicine and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  8. 8Washington University, St Louis
  9. 9Department of Genetics, The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
  10. 10McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA
  11. 11Arc Institute, Palo Alto, CA, USA
  12. 12Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
  13. 13Univ. of California San Diego
  14. 14Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA, USA
  15. 15Department of Medicine, University of California, School of Medicine, La Jolla, CA, USA
  16. 16Department of Neurobiology and Behavior, University of California, Irvine, CA, USA
  17. 17Department of Neurology, University of California, Irvine School of Medicine, Irvine, CA, USA
  18. 18The Center for Neural Circuit Mapping, University of California, Irvine, CA, USA
  19. 19New York Genome Center, New York, NY, USA
  20. 20Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
Open at sourceDOICite

Abstract

Age-related cognitive decline is associated with altered physiology of the hippocampus. While changes in gene expression have been observed in aging brain, the regulatory mechanisms underlying these changes remain underexplored. We generated single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D genome data from 40 human hippocampal tissues spanning adult lifespan. We observed a striking loss of astrocytes, OPC, and endothelial cells during aging, including astrocytes that play a role in regulating synapses. Microglia undergo a dramatic switch from a homeostatic state to a primed inflammatory state through DNA methylome and 3D genome reprogramming. Aged cells experience erosion of their 3D genome architecture. Our study identifies age-associated changes in cell types/states and gene regulatory features that provide insight into cognitive decline during human aging.

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Cite

BibTeXRIS
BibTeX
@article{zemke2026epigenetic,
  title = {{Epigenetic and 3D genome reprogramming during the aging of the human hippocampus}},
  author = {Nathan R. Zemke and Seo Yeon Lee and Sainath Mamde and Bing Yang and Nicole C. Berchtold and B. Maximiliano Garduño and Hannah S. Indralingam and Weronika M. Bartosik and Pik Ki Lau and Keyi Dong and Emily Hsu and Amanda Yang and Yasmine Tani and Chumo Chen and Qiurui Zeng and Varun Ajith and Liqi Tong and Chanrung Seng and Daofeng Li and Ting Wang and Jingtian Zhou and Joseph R. Ecker and Christopher K. Glass and Carl W. Cotman and Xiangmin Xu and Bing Ren},
  journal = {Science},
  year = {2026},
  month = jul,
  doi = {10.1126/science.adt8307},
  url = {https://doi.org/10.1126/science.adt8307},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Epigenetic and 3D genome reprogramming during the aging of the human hippocampus
AU  - Nathan R. Zemke
AU  - Seo Yeon Lee
AU  - Sainath Mamde
AU  - Bing Yang
AU  - Nicole C. Berchtold
AU  - B. Maximiliano Garduño
AU  - Hannah S. Indralingam
AU  - Weronika M. Bartosik
AU  - Pik Ki Lau
AU  - Keyi Dong
AU  - Emily Hsu
AU  - Amanda Yang
AU  - Yasmine Tani
AU  - Chumo Chen
AU  - Qiurui Zeng
AU  - Varun Ajith
AU  - Liqi Tong
AU  - Chanrung Seng
AU  - Daofeng Li
AU  - Ting Wang
AU  - Jingtian Zhou
AU  - Joseph R. Ecker
AU  - Christopher K. Glass
AU  - Carl W. Cotman
AU  - Xiangmin Xu
AU  - Bing Ren
PY  - 2026
DA  - 2026/07/23
JO  - Science
DO  - 10.1126/science.adt8307
UR  - https://doi.org/10.1126/science.adt8307
AB  - Age-related cognitive decline is associated with altered physiology of the hippocampus. While changes in gene expression have been observed in aging brain, the regulatory mechanisms underlying these changes remain underexplored. We generated single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D genome data from 40 human hippocampal tissues spanning adult lifespan. We observed a striking loss of astrocytes, OPC, and endothelial cells during aging, including astrocytes that play a role in regulating synapses. Microglia undergo a dramatic switch from a homeostatic state to a primed inflammatory state through DNA methylome and 3D genome reprogramming. Aged cells experience erosion of their 3D genome architecture. Our study identifies age-associated changes in cell types/states and gene regulatory features that provide insight into cognitive decline during human aging.
SN  - 0036-8075
SN  - 0193-4511
SN  - 1095-9203
ER  -