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Abstract: MicroRNAs (miRNAs) are endogenous noncoding RNAs that downregulate gene expression by inhibiting translation or promoting mRNA degradation. Although over one-third of miRNAs are located within the intronic regions of transcription units, the expression of such “intron-derived” (or “intronic”) miRNAs and their relationship with their host gene remain a mystery. Here, we show that miR-483-5p, which is located within the second intron of the insulin-like growth factor (Igf2) gene, is downregulated in mouse Hepa1–6 cells in a direct correlation with the Igf2 transcript by chromeceptin, an inhibitor of Igf2 at the transcriptional level. Furthermore, miR-483-5p overexpression and knockdown regulates the suppressor of cytokine signalling 3 (Socs3) and Igf2 mRNAs, respectively. Finally, Socs3, a key putative leptin-resistant factor in obesity, is identified as a direct target of miR-483-5p. These data suggest that miR-483-5p can be coexpressed together with its host gene, Igf2, and revealed the link between this miRNA and the IGF2 growth factor. In addition, these observations not only provide supporting evidence for the codependent expression of intronic miRNAs and their host genes in vitro, but also give insight into the role of miR-483-5p in metabolism regulation and tumourigenesis. [ABSTRACT FROM AUTHOR]

The composition of skeletal muscle fiber types affects the quality of livestock meat and human athletic performance and health. L-arginine (Arg), a semi-essential amino acid, has been observed to promote the formation of slow-twitch muscle fibers in animal models. However, the precise molecular mechanisms are still unclear. This study investigates the role of Arg in skeletal muscle fiber composition and mitochondrial function through the mTOR signaling pathway. In vivo, 4-week C56BL/6J male mice were divided into three treatment groups and fed a basal diet supplemented with different concentrations of Arg in their drinking water. The trial lasted 7 weeks. The results show that Arg supplementation significantly improved endurance exercise performance, along with increased SDH enzyme activity and upregulated expression of the MyHC I, MyHC IIA, PGC-1α, and NRF1 genes in the gastrocnemius (GAS) and quadriceps (QUA) muscles compared to the control group. In addition, Arg activated the mTOR signaling pathway in the skeletal muscle of mice. In vitro experiments using cultured C2C12 myotubes demonstrated that Arg elevated the expression of slow-fiber genes (MyHC I and Tnnt1) as well as mitochondrial genes (PGC-1α, TFAM, MEF2C, and NRF1), whereas the effects of Arg were inhibited by the mTOR inhibitor rapamycin. In conclusion, these findings suggest that Arg modulates skeletal muscle fiber type towards slow-twitch fibers and enhances mitochondrial functions by upregulating gene expression through the mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Superenhancer usages in single cancer form such as colorectal cancer (CRC) may provide novel efficient targeting candidates. It is unclear whether CRC contains recurrent superenhancers that confer a predisposition to malignancy. We investigated the superenhancer profile of CRC cell line HCT116 and compared it to that of a healthy sigmoid colon. We found that HCT116 had lost most of the normal colon superenhancer activities but gained a new set of tumor-favoring superenhancers that facilitate tumor proliferation, growth signalling, and hypoxia resistance. Inhibiting the superenhancers by JQ-1 treatment had significantly decreased the colony formation capability of HCT116. Then, by comparing the superenhancer genes and robust CRC upregulated genes, we identified a superenhancer associated with a common CRC upregulated oncogene, POU5f1B. POU5f1B overexpression is related to the worse outcome in CRCs. Via performing ChIP-PCR in 35 clinical samples and investigating CRC anti-H3K27ac ChiP-seq public dataset consisting of 36 samples, we further identified that the superenhancer of oncogene POU5F1B is recurrently activated in CRCs, taking 62 and 72 per cent, respectively. Moreover, JQ-1 treatment successfully inhibited the POU5F1B expression in 5 out of 6 POU5F1B superenhancer-positive samples. Therefore, we concluded that the superenhancer activation of POU5F1B contributes partially to its high expression in CRCs, in addition to the well-known gene amplification aetiology. [ABSTRACT FROM AUTHOR]

Cobalt is an essential micronutrient but is toxic when present in excess. To study cobalt homeostasis we performed a genome-wide screen for deletion strains that show sensitivity or resistance to CoCl. Among 54 cobalt-sensitive strains, 18 are supersensitive strains, which are involved in histidine biosynthetic process, ubiquitination, mitochondria function, membrane trafficking, transporter and a variety of other known functions or still unknown functions. Furthermore, we identified 56 cobalt-resistant deletion strains, which are mainly involved in mitochondria function, signal transduction, ubiquitination, and gene expression and chromatin remodeling. Notably, deletion of the zhf1 gene, encoding a zinc ion transporter, confers supersensitivity to cobalt and overexpression of the zhf1 gene confers marked tolerance to cobalt, indicating that Zhf1 play key roles in cobalt detoxification. Interestingly, all the histidine-auxotrophic mutants displayed cobalt sensitivity and deletion of cationic amino acid transporter Cat1, which was shown to be involved in histidine uptake, suppressed the CoCl-sensitive growth defect of the his2 mutants, suggesting that CoCl may be transported into the cell together with histidine via histidine transporters including Cat1. In addition, we obtained results suggesting that the E2 ubiquitin conjugating enzyme Rhp6 and Sty1 stress MAP kinase pathway are involved in the regulation of cobalt homeostasis. Altogether, our genome-wide study demonstrates for the first time the mechanisms of cobalt homeostasis, particularly its uptake and detoxification in fission yeast. [ABSTRACT FROM AUTHOR]