Disrupted Post-Transcriptional Regulation of Gene Expression as a Hallmark of Fatty Liver Progression

It is known that both transcriptional and post-transcriptional mechanisms control messenger RNA (mRNA) levels. Compared to transcriptional regulations, our understanding of how post-transcriptional regulations adapt during fatty liver progression at the whole-transcriptome level is unclear. While traditional RNA-seq analysis uses only reads mapped to exons to determine gene expression, recent studies support the idea that intron-mapped reads can be reliably used to estimate gene transcription. In this study, we analyzed differential gene expression at both the exon and intron levels using two liver RNA-seq datasets from mice that were fed a high-fat diet for seven weeks (mild fatty liver) or thirty weeks (severe fatty liver). We found that the correlation between gene transcription and mature mRNA levels was much lower in mice with mild fatty liver as compared with mice with severe fatty liver. This result indicates broad post-transcriptional regulations for early fatty liver and such regulations are compromised for severe fatty liver. Specifically, gene ontology analysis revealed that genes involved in synapse organization and cell adhesion were transcriptionally upregulated, while their mature mRNAs were unaffected in mild fatty liver. Further characterization of post-transcriptionally suppressed genes in early fatty liver revealed that their mRNAs harbor a significantly longer 3' UTR, one of the major features that may subject RNA transcripts to nonsense-mediated RNA decay (NMD). We further show that the expression of representative genes that were post-transcriptionally suppressed were upregulated in mice with a hepatocyte-specific defect of NMD. Finally, we provide data supporting a time-dependent decrease in NMD activity in the liver of a diet-induced metabolic-dysfunction-associated fatty liver disease mouse model. In summary, our study supports the conclusion that NMD is essential in preventing unwanted/harmful gene expression at the early stage of fatty liver and such a mechanism is lost due to decreased NMD activity in mice with severe fatty liver.