Roger Seheult, MD
🚨 Only in women! A previously unrecognized female-biased chimeric RNA in human blood called UBA1-CDK16 predicts severity of C19 and innate immunity! Chimeric RNAs are transcripts made by joining RNA pieces from two different genes. They were once thought to mostly occur in cancer because of DNA rearrangements, but this study shows that some chimeric RNAs can arise normally through RNA processing. Researchers analyzed blood RNA data and found that UBA1-CDK16 is strongly expressed in females but usually absent in males. Both genes are on the X chromosome, and the transcript appears to come from the inactive X chromosome, which females have but males generally do not. This was supported by findings that it was present in people with Klinefelter syndrome (XXY) but absent in a person with Turner syndrome (X only). Mechanistically, the RNA is produced by transcriptional read-through, where transcription continues from UBA1 into the neighboring CDK16 gene. However, read-through alone occurs in both sexes. The key female-specific step is a special chromatin loop on the inactive X chromosome that brings splice sites together and allows the mature UBA1-CDK16 chimeric RNA to form. Functionally, UBA1-CDK16 is enriched in myeloid immune cells, such as neutrophils and monocytes. When researchers knocked it down during blood cell development, more myeloid cells formed. This suggests that UBA1-CDK16 may normally act as a brake on excessive myeloid differentiation and inflammation in females. The study also examined COVID-19. Female patients with more severe COVID-19 were more likely to lose UBA1-CDK16 expression. Those lacking it had higher neutrophil counts and a higher neutrophil-to-lymphocyte ratio, a marker associated with worse COVID-19 outcomes. Overall, the study suggests that female-specific RNA processing from the inactive X chromosome may add another layer to sex differences in immunity. UBA1-CDK16 may help regulate inflammatory myeloid responses and could potentially become a biomarker in infectious or autoimmune diseases. https://www.science.org/doi/10.1126/sciadv.adz9784