Volume 32, No 11, Nov 2022

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 32 Issue 11, November 2022: 1008-1021

ORIGINAL ARTICLES

Single-cell epigenome analysis reveals age-associated decay of heterochromatin domains in excitatory neurons in the mouse brain

Yanxiao Zhang^1,2,†,* , Maria Luisa Amaral^3,† , Chenxu Zhu¹ , Steven Francis Grieco⁴ , Xiaomeng Hou⁵ , Lin Lin⁵ , Justin Buchanan⁵ , Liqi Tong⁴ , Sebastian Preissl^5,6 , Xiangmin Xu^4,7,* , Bing Ren^1,5,8,9,*

¹Ludwig Institute for Cancer Research, La Jolla, CA, USA
²School of Life Sciences, Westlake University, Hangzhou, China
³Bioinformatics and Systems Biology Graduate Program, University of California San Diego, La Jolla, CA, USA
⁴Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, USA
⁵Center for Epigenomics, University of California San Diego, La Jolla, CA, USA
⁶Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg, Germany
⁷The Center for Neural Circuit Mapping, University of California, Irvine, CA, USA
⁸Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA
⁹Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA
^†These authors contributed equally: Yanxiao Zhang, Maria Luisa Amaral
Correspondence: Yanxiao Zhang(zhangyanxiao@westlake.edu.cn)Xiangmin Xu(xiangmix@hs.uci.edu)Bing Ren(biren@ucsd.edu)

Loss of heterochromatin has been implicated as a cause of pre-mature aging and age-associated decline in organ functions in mammals; however, the specific cell types and gene loci affected by this type of epigenetic change have remained unclear. To address this knowledge gap, we probed chromatin accessibility at single-cell resolution in the brains, hearts, skeletal muscles, and bone marrows from young, middle-aged, and old mice, and assessed age-associated changes at 353,126 candidate cis-regulatory elements (cCREs) across 32 major cell types. Unexpectedly, we detected increased chromatin accessibility within specific heterochromatin domains in old mouse excitatory neurons. The gain of chromatin accessibility at these genomic loci was accompanied by the cell-type-specific loss of heterochromatin and activation of LINE1 elements. Immunostaining further confirmed the loss of the heterochromatin mark H3K9me3 in the excitatory neurons but not in inhibitory neurons or glial cells. Our results reveal the cell-type-specific changes in chromatin landscapes in old mice and shed light on the scope of heterochromatin loss in mammalian aging.

https://doi.org/10.1038/s41422-022-00719-6

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