Circular RNAs (circRNAs) are a newly appreciated class of RNAs found across phyla that are generated most commonly from back-splicing of protein-coding exons. Recent profiling of circRNAs genome-wide has shown that hundreds of circRNAs dramatically increase in expression during aging in the brains of multiple organisms. No other class of transcripts has been found to show such a strong correlation with aging as circRNAs-could they be playing a role in the aging process? Here, we discuss the different methods used to profile circRNAs and discuss current limitations of these approaches. We argue that age-related increases in global circRNA levels likely result from their high stability. The functions of circRNAs are only beginning to emerge, and it is an open question whether circRNA accumulation impacts the aging brain. We discuss experimental approaches that could illuminate whether age-accumulation of circRNAs are detrimental or protective to the aging brain.

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Circular RNAs (circRNAs) are highly expressed in the brain and their expression increases during neuronal differentiation. The factors regulating circRNAs in the developing mouse brain are unknown. NOVA1 and NOVA2 are neural-enriched RNA-binding proteins with well-characterized roles in alternative splicing. Profiling of circRNAs from RNA-seq data revealed that global circRNA levels were reduced in embryonic cortex of Nova2 but not Nova1 knockout mice. Analysis of isolated inhibitory and excitatory cortical neurons lacking NOVA2 revealed an even more dramatic reduction of circRNAs and establishes a widespread role for NOVA2 in enhancing circRNA biogenesis. To investigate the cis-elements controlling NOVA2-regulation of circRNA biogenesis, we generated a backsplicing reporter based on the Efnb2 gene. We found that NOVA2-mediated backsplicing of circEfnb2 was impaired when YCAY clusters located in flanking introns were mutagenized. CLIP (cross-linking and immunoprecipitation) and additional reporter analyses demonstrated the importance of NOVA2 binding sites located in both flanking introns of circRNA loci. NOVA2 is the first RNA-binding protein identified to globally promote circRNA biogenesis in the developing brain.

Group B streptococci (GBS) are Gram-positive bacteria that are a leading cause of neonatal infections. Most invasive isolates are β-hemolytic, and hemolytic activity is critical for GBS virulence. Although nonhemolytic GBS strains are occasionally isolated, they are often thought to be virulence attenuated. In this study, we show that a nonhemolytic GBS strain (GB37) isolated from a septic neonate exhibits hypervirulence. Substitution of tryptophan to leucine (W297L) in the sensor histidine kinase CovS results in constitutive kinase signaling, leading to decreased hemolysis and increased activity of the GBS hyaluronidase, HylB. These results describe how nonpigmented and nonhemolytic GBS strains can exhibit hypervirulence.

CircRNAs are a recently appreciated class of RNAs generated by backsplicing (Li et al., 2018). Most characterized circRNAs are produced from exons of protein-coding genes (Zhang et al., 2014).CircRNAs lack free ends, resulting in greater resistance to exoribonuclease digestion compared to their linear RNA counterparts (Jeck et al., 2013). Interestingly, circRNAs were found to accumulate in the brains of Drosophila and rodents during aging (Gruner et al., 2016;