Transcriptome signature of miRNA-26b KO mouse model suggests novel targets

Abstract

Background MicroRNAs (miRNAs) are short (20–24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. One of the miRNAs that has been shown to play a role in various pathologies like cancer, neurological disorders and cardiovascular diseases is miRNA-26b. However, these studies only demonstrated rather ambiguous associations without revealing a causal relationship. Therefore, the aim of this study is to establish and validate a mouse model which enables the elucidation of the exact role of miRNA-26b in various pathologies. Results A miRNA-26b-deficient mouse model was established using homologous recombination and validated using PCR. miRNA-26b-deficient mice did not show any physiological abnormalities and no effects on systemic lipid levels, blood parameters or tissue leukocytes. Using next generation sequencing, the gene expression patterns in miRNA-26b-deficient mice were analyzed and compared to wild type controls. This supported the already suggested role of miRNA-26b in cancer and neurological processes, but also revealed novel associations of miRNA-26b with thermogenesis and allergic reactions. In addition, detailed analysis identified several genes that seem to be highly regulated by miRNA-26b, which are linked to the same pathological conditions, further confirming the role of miRNA-26b in these pathologies and providing a strong validation of our mouse model. Conclusions miRNA-26b plays an important role in various pathologies, although causal relationships still have to be established. The described mouse model of miRNA-26b deficiency is a crucial first step towards the identification of the exact role of miRNA-26b in various diseases that could identify miRNA-26b as a promising novel diagnostic or even therapeutic target in a broad range of pathologies.

MicroRNA-26b protects against MASH development in mice and can be efficiently targeted with lipid nanoparticles

“…MiRs have been indicated to play a critical role in the development of several pathologies, including MASH. While the role of miR-26b has already been investigated in various cardio-metabolic diseases [5], its role in MASH remained unknown so far. Therefore, this study focused on the role of miR-26b in MASH showing that mice deficient in miR-26b presented with a higher hepatic lipid content, higher levels of pro-inflammatory cytokines, and an increased number of infiltrated macrophages in the liver and exacerbated hepatic fibrosis.…”

“…Apoe -/- Mir26b -/- mice were generated as described in [5]. Apoe -/- mice were used as control and all mice were on C57BL/6J background for more than 10 generations.…”

“…Although many miRs have been examined in MASLD, the possible pathogenic involvement of numerous others, remains unknown. One of the miRs that has been researched in a number of pathologies, including cancer, cardiovascular illnesses, and neurological disorders is miR-26b [5]. However, so far very little is known about the function of miR-26b in the liver and MASH.…”

“…The findings above show that miR-26b may play a role in the pathogenesis of MASH, although no study has determined its exact causal involvement in MASH development. In this investigation, we used previously described miR-26b knockout mice [5] and myeloid cell-specific miR-26b knockout mice to clarify the role of miR-26b in hepatic lipid metabolism, inflammation, and fibrogenesis. Furthermore, lipid nanoparticles (LNPs), which act as clinically and therapeutically relevant vehicles [8], loaded with miR-26b mimics were used to restore miR-26b levels in mice as well as in human precision-cut liver slices to investigate its therapeutic potential.…”

Correction to: Transcriptome signature of miRNA-26b KO mouse model suggests novel targets

“…Following publication of the original article [ 1 ], the authors identified an error in the author name of Ronald Naumann.…”