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

• 成果类型: Article
• 署名作者: Zemke, Nathan R.; Lee, Seoyeon; Mamde, Sainath; Yang, Bing; Berchtold, Nicole; Garduno, B. Maximiliano; Indralingam, Hannah S.; Bartosik, Weronika M.; Lau, Pik Ki; Dong, Keyi; Hsu, Emily; Yang, Amanda; Tani, Yasmine; Chen, Chumo; Zeng, Qiurui; Ajith, Varun; Tong, Liqi; Seng, Chanrung; Li, Daofeng; Wang, Ting; Zhou, Jingtian; Ecker, Joseph R.; Glass, Christopher K.; Cotman, Carl W.; Xu, Xiangmin; Ren, Bing
• 署名单位: University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California Irvine; University of Southern California; University of Southern California; Washington University (WUSTL); Washington University (WUSTL); Salk Institute; Salk Institute; Howard Hughes Medical Institute; University of California System; University of California San Diego; University of California System; University of California Irvine; University of California System; University of California Irvine; University of California System; University of California Irvine; Columbia University; Cornell University; Weill Cornell Medicine; NewYork-Presbyterian Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adt8307
• 发表日期: 2026-07-23
• 页码: eadt8307
• 关键词: life-span; microglia; methylation; association; astrocytes; expression; monocytes; domains; atrophy; HEALTH

摘要

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.