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

Li Ma, Feng Wang, Yangping Li, Jing Wang, Qing Chang, Yuanning Du, Jotham Sadan, Zhen Zhao, Guoping Fan (), Bing Yao () and Jian-Fu Chen ()
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Li Ma: University of Southern California
Feng Wang: Emory University School of Medicine
Yangping Li: Emory University School of Medicine
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 School of Medicine
Jian-Fu Chen: University of Southern California

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43497-4

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