Biology subjects

Jaso-Vera, M. E.

Publications and source records attributed to Jaso-Vera, M. E..

3 recordsLinked to original sources

bioRxiv2025

Suppression of hepatic amino acid catabolism by the human-specific lncRNA hLMR1

Amino acid (AA) catabolism and ureagenesis in the liver are essential for maintaining systemic nitrogen homeostasis. Patients with metabolic-associated fatty liver disease (MAFLD) exhibit impaired hepatic AA catabolism and urea production, accompanied by repression of genes governing these pathways. The molecular basis of this repression remains unknown. Here, we identify the hepatocyte-specific long noncoding RNA hLMR1 as a key suppressor of hepatic AA catabolism. Using a humanized liver mouse model, we show that hLMR1 knockdown broadly upregulates genes involved in AA degradation and ureagenesis. Chromatin isolation by RNA purification (ChIRP) coupled with RNA-seq reveals extensive interactions between hLMR1 and the pre-mRNAs of AA catabolism genes, mediated by a conserved complementary motif within hLMR1 (nucleotides 587-598). In primary human hepatocytes, hLMR1 overexpression inhibits glucagon-induced activation of AA catabolic genes, whereas deletion of the 587-598 region abrogates this effect. Analysis of human liver RNA-seq datasets demonstrates a negative correlation between hLMR1 expression and AA catabolic gene programs in MAFLD. Together, these findings uncover hLMR1 as a previously unrecognized regulator of hepatic nitrogen metabolism, linking lncRNA dysregulation to metabolic dysfunction in MAFLD.

molecular biology↗

bioRxiv2025

Human-Specific Suppression of Hepatic Fatty Acid Catabolism by RNA-Binding Protein HuR

RNA binding proteins (RBPs) play essential roles in all major steps of RNA processing. Genetic studies in human and mouse models support that many RBPs are crucial for maintaining homeostasis in key tissues/organs, but to what extent the function of RBPs is conserved between humans and mice is not clear. Our recent study using a chimeric humanized liver mouse model found that knocking down human HuR in human hepatocytes resulted in a broad upregulation of human genes involved in fatty acid catabolism. This regulation is human-specific, as the knocking down of mouse HuR in the liver of traditional mouse models did not show these effects. To further study this human-specific role of HuR, we co-overexpressed HuR with PPAR, a master transcription factor that promotes fatty acid catabolism, in cultured cells. We found that HuR suppressed the expression of PPAR induced fatty acid catabolism genes in human cells but not in mouse cells. We provide evidence supporting that the human-specific suppressive effect of HuR is independent of PPAR expression or location. The regulatory effects of HuR are also independent of its role in regulating mRNA stability. Using the human HMGCS2 gene as an example, we found that the suppressive effect of HuR cannot be explained by decreased promoter activity. We further provide evidence supporting that HuR suppresses the pre-mRNA processing of HMGCS2 gene, leading to accumulated intron/pre-mRNA expression of HMGCS2 gene. Furthermore, overexpression of HuR blocked and knocking down of HuR sensitized PPAR agonist-induced gene expression. By analyzing published RNA-seq data, we found compromised pre-mRNA processing for fatty acid catabolism genes in patients with fatty liver diseases, which was not observed in mouse fatty liver disease models. Our study supports the model that HuR suppresses the expression of fatty acid catabolism genes by blocking their pre-mRNA processing, which may partially explain the mild effects of PPAR agonists in treating fatty liver diseases in humans as compared with studies in mice.

molecular biology↗

bioRxiv2024

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 the 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 that intron-mapped reads can be reliably used to estimate gene transcription. In this study, we analyzed differential gene expression at both 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 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 comprised 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 the mild fatty liver. Further characterization of post-transcriptionally suppressed genes at early fatty liver revealed that their mRNAs harbor significantly longer 3 UTR, one of the major features that may subject RNA transcripts to non-sense mediated RNA decay (NMD). We further show that the expression of representative genes that were post-transcriptionally suppressed were upregulated in mice with 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 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.

bioinformatics↗