Aberrant alternative splicing in alcoholic hepatitis: regulatory roles of RBPs and sQTLs

Alternative splicing (AS) plays a critical role in gene regulation, contributing to transcriptomic complexity and disease progression.

In this study, we investigated the regulatory effects of AS in alcoholic hepatitis (AH) using transcriptomic data from 41 samples (Normal: 21; AH: 20) from three projects (PRJNA597328, PRJNA600011 and PRJNA656197) from the NCBI database.

A total of 1,061,774 transcripts were identified, of which 42.23% were novel and not annotated in the reference genome, highlighting the diversity of transcriptomic variation in AH. Furthermore, we identified 1,655 aberrant alternative splicing events (AASEs) associated with 1,170 genes, 487 of which were significantly correlated with 22 differentially expressed RNA-binding proteins (RBPs). Additionally, 4,745 splicing quantitative trait loci (sQTLs) were identified in AH, mapped to 2,438 genes enriched in the regulation of some metabolic processes. Notably, several susceptibility sQTL locis were located within known alcoholic liver disease (ALD) associated genes, including GAB1, TJP2 and RCAN1. These findings suggest that AS, through its regulation by RBPs and genetic variants (sQTLs), significantly influences key biological processes in AH, including fatty acid degradation and ferroptosis, processes that are central to the clinical manifestations of AH.

This study provides new insights into the molecular mechanisms underlying AH, emphasizing the importance of AS and its regulatory factors in disease progression.