A Sex-Specific Chimeric RNA in Female Immune Regulation: Case Study

Recent studies have highlighted that many diseases and conditions, including aging, cancer, and infectious diseases, can manifest differently in males and females. Over the past years, sex-specific transcriptomes have been uncovered in stem cells, nervous system, and immune system. However, chimeric RNAs formed by intergenic splicing are less appreciated, but provide another critical layer of RNA diversification. Leveraging the analysis of RNA-Seq data and the validation of outcomes across a cohort of over 1200 blood samples, we discovered UBA1-CDK16, a female-specific chimeric transcript. In contrast, both parental genes exhibit expression in males and females. Mechanistically, UBA1-CDK16 arises through cis-splicing between two adjacent X-linked genes, originating from the inactive X chromosome. Functionally, our investigation reveals that UBA1-CDK16 is enriched in the myeloid lineage and plays a regulatory role in myeloid differentiation. Notably, female COVID-19 patients who tested negative for this chimeric transcript displayed higher counts of neutrophils, highlighting its potential role in disease pathogenesis. These findings support the notion that chimeric RNAs represent a new repertoire of transcripts that can be regulated independently from the parental genes, and a new class of RNA variance with potential implications in sexual dimorphism and immune responses.