Dynamic intron retention modulates gene expression in the monocytic differentiation pathway.

Monocytes play a crucial role in maintaining homeostasis and mediating a successful innate immune response. They also act as central players in diverse pathological conditions, thus making them an attractive therapeutic target. Within the bone marrow, monocytes arise from a committed precursor termed cMoP (Common Monocyte Progenitor). However, molecular mechanisms that regulate the differentiation of cMoP to various monocytic subsets remain unclear. Herein, we purified murine myeloid precursors for deep poly-A enriched RNA sequencing to understand the role of alternative splicing in the development and differentiation of monocytes under homeostasis. Our analyses revealed intron retention to be the major alternative splicing mechanism involved in the monocyte differentiation cascade, especially in the differentiation of Ly6Chi monocytes to Ly6Clo monocytes. Furthermore, we found that the key genes regulated by intron retention in the differentiation of murine Ly6Chi to Ly6Clo monocytes were also conserved in humans. Our data highlight the unique role of intron retention in the regulation of the monocytic differentiation pathway.