Genome-wide identification of abnormal alternative splicing and RBP regulators in intestinal failure-associated liver...

Prolonged or inappropriate use of total parenteral nutrition (TPN) may lead to the development of intestinal failure-associated liver disease (IFALD), which causes significant morbidity in TPN recipients. However, the underlying mechanism remains unclear.

Transcriptomic data of liver samples from Sprague‒Dawley rats treated with TPN or standard chow with 0.9% saline were downloaded from the Sequence Read Archive (SRA). The alternative splicing (AS) events and regulated alternative splicing (RAS) events between IFALD and normal samples were defined and quantified using the SUVA pipeline. The frequency and read proportion of the SUVA AS events (pSAR) of each AS event were calculated to identify the dominant transcripts.

A total of 268 dominant IFALD-RAS events with pSAR ≥ 50 % were identified. The genes associated with these RAS events were enriched mainly in the biological process of cell matrix adhesion. Then, we identified 25 RAS events associated with cell adhesion, including Afdn in AS events clustered at 3p3777. Moreover, we found that the infiltration of M2 macrophages was significantly greater in IFALD livers than in normal livers. Clualt5p19266:Supt20h was significantly positively correlated with the infiltration of M2 macrophages. Finally, we identified 33 differentially expressed RNA-binding proteins (DE-RBPs) and constructed a regulatory network between RBPs and co-disturbed RAS events.

Changes in AS may play vital roles in the pathogenesis of IFALD under TPN. The Mbnl3-Zmynd11 axis may be a potential therapeutic target for IFALD.