A global analysis on the differential regulation of RNA binding proteins (RBPs) by TNF-α as potential modulators of metabolic syndromes.

Metabolic syndrome (MetS) is associated with a group of conditions, which enhances the risk of diabetes, heart diseases and stroke in the affected individuals. Earlier reports from our lab have shown that Tumor necrosis factor-α (TNF-α) significantly modulates the expression of 56 genes at the alternative splicing level which are involved in various signaling and metabolic pathways (MetS genes) connected to MetS. These MetS genes were predicted to interact with various RNA-binding proteins (RBPs) when exposed to TNF-α, resulting changes in their alternative splicing patterns. Here we are presenting data of an RNA-Seq analysis, which identified 1218 unique, and significantly regulated genes by TNF-α, 15% of which are RBPs . Among the 1218 genes, 204 genes have been identified as MetS genes by the ingenuity pathway analysis, and 10% of the MetS genes are found as RBPs. Our results also show that TNF-α changes the phosphorylation status of certain RBPs such as SR proteins, crucial players in alternative splicing, possibly via changing the activation status of certain upstream signaling molecules which also act as upstream kinases for these proteins. Taken together, these findings suggest that TNF-α influences the regulation of the RBPs at the various levels for their expression, which may lead to the alteration of the splicing pattern of the MetS genes. MetS genes acting as RBPs and are modulated by TNF-α, predict the existence of highly interconnected mechanisms which require further analysis to understand their dual roles on the onset of these diseases.