Effects of Srsf3 deletion on gene expression and 3' UTR profiles in macrophages and atherosclerotic plaques [scRNA-seq]

Serine and arginine rich splicing factor 3 (Srsf3) is the smallest member of the serine/arginine rich protein family and directly modulates 3' UTR length, which may impact the stability, localization, and translation efficiency of the mRNAs. Here, we report that genetic ablation of Srsf3 disturbs macrophage maturation from circulating monocytes, thus limiting phagocytosis of low-density lipoproteins and dead cells in plaques, which aggravates atherosclerosis in Apoe-/- mice fed on high-cholesterol diet for 12 weeks. Deficiency in Srsf3 suppresses mitochondrial translation by shortening 3' UTRs of mitochondrial aminoacyl-tRNA synthetase, consequently leading to mitochondrial dysfunction in macrophages. Our study reveals that Srsf3-mediated distal polyadenylation site usage is required for mitochondrial translation during macrophage maturation, which may have broad pathophysiological implications for atherosclerosis. Overall design: To characterize the effects of Srsf3 on gene expression and 3' UTR profiles in lesional macrophages, we performed 3' end sequencing and scRNA-seq of plaque cells in Apoe-/- mice with or without myeloid Srsf3 deletion after high-cholesterol diet feeding, as well as 3' end sequencing of murine bone marrow-derived macrophages treated with oxLDL.