Brain methylome remodeling selectively regulates neuronal activity genes linking to emotional behaviors in mice exposed to maternal immune activation

• Type of Material: Article
• Authors: Li Ma, University of Southern California; Feng Wang, Emory University; Yangping Li, Emory University; Jing Wang, University of California Los Angeles; Qing Chang, University of Southern California; Yuanning Du, University of Southern California; Jotham Sadan, University of Southern California; Zhen Zhao, University of Southern California; Guoping Fan, University of California Los Angeles; Bing Yao, Emory University; Jian-Fu Chen, University of Southern California
• Language: English
• Date: 2023-11-29
• Publisher: Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1038/s41467-023-43497-4
• Title of Journal or Parent Work: Nature Communications
• Volume: 14
• Start Page: 7829
• Grant/Funding Information: Chen laboratory is supported by funds from the Associate Dean of Research Fund from the Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry at the University of Southern California, as well as grants R01DE030901 (J.C.), R21AG075665 (J.C.), and R21AG070681 (J.C.) from the National Institute of Health. L. M. is a post-doctoral fellowship recipient of California Institute for Regenerative Medicine (CIRM) training grant.
• Keywords: induced-maternal immune activation; genetics of the nervous system; Zika virus; epigenetics; depression; early life experience; behaviour; anxiety
• Research Categories: Psychology, Developmental; Biology, Genetics; Psychology, Behavioral

Abstract

How early life experience is translated into storable epigenetic information leading to behavioral changes remains poorly understood. Here we found that Zika virus (ZIKV) induced-maternal immune activation (MIA) imparts offspring with anxiety- and depression-like behavior. By integrating bulk and single-nucleus RNA sequencing (snRNA-seq) with genome-wide 5hmC (5-hydroxymethylcytosine) profiling and 5mC (5-methylcytosine) profiling in prefrontal cortex (PFC) of ZIKV-affected male offspring mice, we revealed an overall loss of 5hmC and an increase of 5mC levels in intragenic regions, associated with transcriptional changes in neuropsychiatric disorder-related genes. In contrast to their rapid initiation and inactivation in normal conditions, immediate-early genes (IEGs) remain a sustained upregulation with enriched expression in excitatory neurons, which is coupled with increased 5hmC and decreased 5mC levels of IEGs in ZIKV-affected male offspring. Thus, MIA induces maladaptive methylome remodeling in brain and selectively regulates neuronal activity gene methylation linking to emotional behavioral abnormalities in offspring.