Abstract
Fetal alcohol spectrum disorders (FASD) are heterogeneous disorders associated with alcohol exposure to the developing fetus that are characterized by a range of adverse neurodevelopmental deficits. Despite the numerous genomics and genetic studies on FASD models, the comprehensive molecular understanding of the mechanisms that underlie FASD-related neurodevelopmental deficits remains elusive. Circular RNAs (circRNAs) are a subtype of long non-coding RNAs that are derived from back-splicing and covalent joining of exons and/or introns of protein-coding genes. Recent studies have shown that circRNAs are highly enriched in the brain, where they are developmentally regulated. However, the role of the majority of brain-enriched circRNAs in normal and pathological brain development and function has not been explored yet. Here we carried out the first systematic profiling of circRNA expression in response to prenatal alcohol exposure (PAE) in male and female embryonic day 18 (E18) whole brains. We observed that the changes in circRNA expression in response to PAE were notably sex-specific and that PAE tended to erase most of the sex-specificity in circRNA expression present in control (saccharin-treated) mice. On the other hand, RNA sequencing (RNA-seq) in the same samples showed that changes in protein-coding gene expression were not predominantly sex-specific. Using circRNA quantitative real-time PCR (qRT-PCR), we validated that circSatb2, which is generated from the special AT-rich sequence-binding protein 2 (Satb2) gene, is significantly upregulated in the brain of E18 male PAE mice. We also show that circPtchd2, a circRNA synthesized from dispatched RND transporter family member 3 (Disp3, also known as Ptchd2), exhibits significantly higher expression in E18 control but not PAE female mouse brain relative to males. Taken together, our results demonstrate that PAE differentially alters circRNA expression in the developing brain in a sex-specific manner.
Highlights
Fetal alcohol spectrum disorder (FASD) encompasses a range of heterogeneous developmental disorders with nervous system abnormalities including learning and memory deficits (Brady et al, 2012; Carter et al, 2016), alterations in behavioral flexibility (Marquardt et al, 2020), and reduced brain volume and cortical thickness (Treit et al, 2017)
A novel subset of long ncRNAs (lncRNAs) known as circular RNAs, which are predominately derived from the covalent joining of back-spliced exons, were found to be enriched in the mammalian brain and abundantly expressed in synapses (Hansen et al, 2013; Memczak et al, 2013; Guo et al, 2014; Rybak-Wolf et al, 2014; You et al, 2015)
CircRNAs are generated from exons and introns of proteincoding genes and display neuronal activity- and developmental stage-dependent expression profiles (Rybak-Wolf et al, 2014; Gruner et al, 2016; Reddy et al, 2017; Zimmerman et al, 2020). Their biogenesis has been shown to be promoted by interactions between complementary intronic repeat sequences and the binding of RNA-binding proteins (RBPs) close to the circRNA splice junction, but inhibited by factors that promote linear splicing and proteins that can disrupt the interactions between the intronic complementary regions (Li et al, 2018; Kristensen et al, 2019)
Summary
Fetal alcohol spectrum disorder (FASD) encompasses a range of heterogeneous developmental disorders with nervous system abnormalities including learning and memory deficits (Brady et al, 2012; Carter et al, 2016), alterations in behavioral flexibility (Marquardt et al, 2020), and reduced brain volume and cortical thickness (Treit et al, 2017). CircRNAs are generated from exons and introns of proteincoding genes and display neuronal activity- and developmental stage-dependent expression profiles (Rybak-Wolf et al, 2014; Gruner et al, 2016; Reddy et al, 2017; Zimmerman et al, 2020) Their biogenesis has been shown to be promoted by interactions between complementary intronic repeat sequences and the binding of RNA-binding proteins (RBPs) close to the circRNA splice junction, but inhibited by factors that promote linear splicing and proteins that can disrupt the interactions between the intronic complementary regions (Li et al, 2018; Kristensen et al, 2019). CircRNA expression has been shown to be altered in various psychiatric disorders (Zimmerman et al, 2020), autism (Chen et al, 2020), cocaine addiction (Bu et al, 2019), and Alzheimer’s disease (Dube et al, 2019)
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