63. A female-specific chimeric RNA with differential expression in COVID patients

Clinical statistics show that women and men act differently in various diseases. In the recent coronavirus disease 2019 (COVID-19) pandemic, scientists reported that men suffered more severe symptoms and higher mortality than women. Chimeric RNA, as a new layer of RNA diversification, is defined as a hybrid transcript containing exons from two originally separate genes. To understand the fundament of sex-biased COVID-19 phenotypes, we aim to discover sex-specific chimeric RNAs and their potential functions. Here, we identified a female-specific chimeric transcript U-C by analyzing 7,059 RNA-seq datasets of the Genotype-Tissue Expression (GTEx) Project. This chimeric transcript was validated to be specific to females and enriched in circulating blood cells. In contrast, the parental genes are expressed in both males and females. We then detected differential expression of U-C in 90 female COVID patients from the Tongji Hospital in China. U-C expression was detected at a baseline range in all asymptomatic patients while significantly decreased in patients with severe symptoms. It has been reported that female COVID patients had fewer circulating neutrophils and monocytes. We then investigated the potential function of U-C during in vitro myeloid differentiation. A larger population of CD11b+ myeloid cells was observed after knocking down U-C specifically. Furthermore, we investigated the mechanism of this chimeric transcript formation. U-C was found to be a product of cis-splicing between two X-linked neighboring genes and expressed exclusively from the inactive X chromosome, which is mediated by an intergenic chromatin loop formed between the U-C junction sites. Clinical statistics show that women and men act differently in various diseases. In the recent coronavirus disease 2019 (COVID-19) pandemic, scientists reported that men suffered more severe symptoms and higher mortality than women. Chimeric RNA, as a new layer of RNA diversification, is defined as a hybrid transcript containing exons from two originally separate genes. To understand the fundament of sex-biased COVID-19 phenotypes, we aim to discover sex-specific chimeric RNAs and their potential functions. Here, we identified a female-specific chimeric transcript U-C by analyzing 7,059 RNA-seq datasets of the Genotype-Tissue Expression (GTEx) Project. This chimeric transcript was validated to be specific to females and enriched in circulating blood cells. In contrast, the parental genes are expressed in both males and females. We then detected differential expression of U-C in 90 female COVID patients from the Tongji Hospital in China. U-C expression was detected at a baseline range in all asymptomatic patients while significantly decreased in patients with severe symptoms. It has been reported that female COVID patients had fewer circulating neutrophils and monocytes. We then investigated the potential function of U-C during in vitro myeloid differentiation. A larger population of CD11b+ myeloid cells was observed after knocking down U-C specifically. Furthermore, we investigated the mechanism of this chimeric transcript formation. U-C was found to be a product of cis-splicing between two X-linked neighboring genes and expressed exclusively from the inactive X chromosome, which is mediated by an intergenic chromatin loop formed between the U-C junction sites.