ABSTRACT: IgA nephropathy (IgAN), characterized by the aberrant deposition of IgA immune complexes, is the most common primary glomerular disease (PGD) which progresses to renal failure. As a receptor of IgA and potential RNA binding protein (RBP), transferrin receptor1(TFRC) plays a key part in IgAN. However, the molecular mechanism of TFRC in the development of IgAN remains unclear. In the current study, TFRC was overexpressed in human renal tubular mesangial cells (HRMCs), followed by RNA-sequencing (RNA-seq) and improved RNA immunoprecipitation sequencing (iRIP-seq) to analyze and identify potential RNA targets at the transcription and alternative splicing (AS) levels regulated by TFRC. TFRC regulates the expression levels of genes positively associated with cell cycle and proliferation. The AS genes regulated by TFRC were enriched in mRNA splicing and DNA repair, consistent with the global AS profile changes by TFRC overexpression (TFRC-OE). Meanwhile, reverse transcription quantitative polymerase chain reaction (RT-qPCR) was conducted to validate TFRC-regulated genes potentially associated with IgAN, including CENPH, FOXM1, KIFC1, TOP2A, FABP4, ID1, KIF20A, ATF3, H19, IRF7, and H1-2 at the expression level and CYGB, MCM7, and HNRNPH1 at the AS level. In addition, iRIP-seq data were analyzed to identify TFRC-bound RNA targets. TFRC regulates the expression and AS levels of a subset of genes by binding to their transcripts, thus playing an important role in IgAN. We validated several TFRC-bound RNA targets with important functions in cell proliferation, including RCC1 and RPPH1. In conclusion, the molecular targets of TFRC were identified in HRMCs, and TFRC may play a key role in IgAN development by binding to RNAs or indirectly regulating genes’ transcriptomic levels, including the expression and AS, further extending the knowledge of the mechanism of TFRC as a clinical therapeutic target.
