Brain methylome remodeling sustains neuronal activity gene expression in mice exposed to maternal immune activation [5mC]
Maternal infections have been linked to various neuropsychiatric disorders that may later emerge in offspring. 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) are key DNA modifications but their roles in maternal infection remain to be elucidated. It has been documented that Zika virus (ZIKV) infection during pregnancy leads to structural brain defects such as microcephaly in offspring. However, whether and how offspring exposed to maternal ZIKV infection develop neurocognitive complications remain largely unknown. Here we report that ZIKV infection during mouse pregnancy leads to offspring with depression- and anxiety-like behaviors, which are transmitted to the next generation. Single nucleus RNA sequencing in prefrontal cortex (PFC) of ZIKV offspring mice revealed cell type-specific gene dysregulation associated with neuropsychiatric lesions. Genome-wide 5hmC, 5mC, and transcriptome profiling in ZIKV PFC revealed an overall loss of 5hmC and an increase of 5mC in intragenic regions, associated with transcriptional changes in key functional genes. Gain-of-5hmC regions were mainly located in intergenic transposable elements (TEs) coupled with decreased 5mC and dynamic TE expression. These results provide the first 5hmC study in maternal infection and suggest that maternal ZIKV infection remodels methylome and gene expression in offspring mouse brains, contributing to transgenerational behavior changes. Overall design: NeuN+ and NeuN- cell population from ZIKA virus treatment and mock group were subject for MeDIP-seq