Elucidating the functional dynamics of DNASE1L2 intron retention in tuberculosis progression

BACKGROUND: Intron retention (IR) is an important biological process associated with disease development. However, the role of IR in the progression of tuberculosis (TB) remains unexplored. Therefore, this study aimed to characterize the dynamic IR landscape during TB progression and elucidate the role of DNASE1L2 -IR in this process. METHODS: We conducted a comprehensive high-throughput sequencing analysis using 1729 samples from 19 public datasets and identified candidate IR events associated with TB progression. We then validated these candidate IR events in three macrophage infection models by quantitative polymerase chain reaction and revealed the underlying molecular mechanisms by investigating the subcellular localization and functional roles of their associated isoforms. RESULTS: In an analysis of 1729 clinical specimens, we found genome-wide intron-splicing reprogramming in host cells during TB progression. Notably, deoxyribonuclease 1 like 2 ( DNASE1L2, a gene encoding deoxyribonuclease)-IR exhibited striking differences among healthy controls, individuals with latent TB infection, and individuals with active TB ( Padj