Cross-organ communication based on non-coding RNA networks leads to cognitive dysfunction in mice

Beyond regulation of mRNAs by individual ncRNA types, like miRNAs, circRNAs or lncRNAs, their interplay as competitive endogenous RNAs (ceRNAs) appears pivotal in diseases. ceRNAs are promising biomarkers in diagnosing diseases as well as in understanding off-target drug mechanisms or developing specific therapeutics. Many diseases are influenced at different molecular levels and across multiple organs, making cross-organ multi-omics interaction studies necessary to holistically understand diseases and their regulation. In our study we applied this approach to the cognitive dysfunction caused by deficiency of functioning tRNA 2'-O-methyltransferase FTSJ1. We investigated the expression changes of mRNA and multiple ncRNA species (miRNAs, lncRNAs, circRNAs) in Ftsj1-deficient versus wild-type C57BL/6 J mice and constructed organ-specific ceRNA networks for the brain, heart, kidney, liver, spleen. Validation of potential ncRNA biomarkers was performed using degradome sequencing as well as qRT-PCR.

The strongest effects of differential expression due to Ftsj1 deficiency were observed in liver and kidney, where especially genes involved in fatty acid metabolism showed altered expression. We reveal a prominent ceRNA network induced by Ftsj1 deficiency in liver and kidney, mediated by four hub-miRNAs (miR-378d, miR-3076-5p, miR-3474, miR-296-3p) enriched with acyl-CoA-related genes, including Acly, Acss2, and Mvk. In contrast, brain tissues showed minimal changes in gene expression, hinting at cross-organ interactions for cognitive dysfunction also supported by previously described phenotypes like muscle weakness in mice with Ftsj1 deficiency.

Our results suggest the involvement of multiple cross-organ regulatory mechanisms for single gene-associated intellectual disability. For FTSJ1 deficiency, this indicates that the cognitive impairment presented by affected human individuals can be associated with metabolic impairment and ceRNA crosstalk along the liver-brain and kidney-brain axes. Our findings provide a new perspective on the development of cognitive impairments caused by mutations of individual genes and underline the importance of multi-omics cross-organ analyses for the development of therapeutics and identification of biomarkers based on ceRNA-mediated networks.