Epigenetic and 3D genome reprogramming during the aging of the human hippocampus
Abstract
Changes in gene expression have been observed in the aging human brain, but our understanding of the underlying regulatory mechanisms remains limited. To unravel these complexities, we analyzed single-nucleus gene expression, chromatin accessibility, DNA methylation, and three-dimensional (3D) chromatin architecture from human hippocampal tissues spanning the adult lifespan. We identified both linear and nonlinear dynamic gene regulatory programs during aging. Between the ages of 50 to 75, embryonic yolk sac–derived microglia were depleted and replaced by cells resembling peripheral blood monocyte–derived microglia. Hippocampal astrocytes decreased substantially with age, including those regulating synaptic transmission. Across cell types, 3D genome architecture underwent global erosion. Our analysis provides insights for how altered gene regulatory programs promote cell type–specific aging phenotypes in the human brain.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (26)
Nathan R. Zemke
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Seoyeon Lee
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Sainath Mamde
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Bing Yang
Nicole Berchtold
Department of Anatomy and Neurobiology, University of California, Irvine School of Medicine, Irvine, CA, USA.
B. Maximiliano Garduño
Department of Anatomy and Neurobiology, University of California, Irvine School of Medicine, Irvine, CA, USA.
Hannah S. Indralingam
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Weronika M. Bartosik
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Pik Ki Lau
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Keyi Dong
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Emily Hsu
Center for Epigenomics, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Amanda Yang
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Yasmine Tani
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Chumo Chen
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Qiurui Zeng
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Varun Ajith
Department of Anatomy and Neurobiology, University of California, Irvine School of Medicine, Irvine, CA, USA.
Liqi Tong
Department of Anatomy and Neurobiology, University of California, Irvine School of Medicine, Irvine, CA, USA.
Chanrung Seng
Department of Genetics, The Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
Daofeng Li
Ting Wang
Department of Radiation Oncology The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital Zhengzhou China
Jingtian Zhou
Joseph R. Ecker
Christopher K. Glass
Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Carl W. Cotman
Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.
Xiangmin Xu
Department of Anatomy and Neurobiology, University of California, Irvine School of Medicine, Irvine, CA, USA.
Bing Ren