The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.

The Lin28/let-7 Axis Regulates Glucose Metabolism

And Beyond由两名活泼的女性设计师约兰达．范登·布洛克（Jolanda vanden Broek）和布丽琦特，亨德里克斯（Brigitte Hendrix）搭档组成，她们于2005年毕业于阿姆斯特丹的里特维尔学术学院（Cerrit Rietveld Academy）的时装设计系，在上学的时候，两人经常一起做命题设计，在合作中渐渐发展成一对无话不谈的亲密搭档，相互之间的沟通也越来越默契。

女性的力量：And Beyond

MicroRNAs (miRNAs) are transcriptional and posttranscriptional regulators involved in nearly all known biological processes in distant eukaryotic clades. Their discovery and functional characterization have broadened our understanding of biological regulatory mechanisms in animals and plants. They show both evolutionary conserved and unique features across Metazoa. Here, we present the current status of the knowledge about the role of miRNA in development, growth, and physiology of teleost fishes, in comparison to other vertebrates. Infraclass Teleostei is the most abundant group among vertebrate lineage. Fish are an important component of aquatic ecosystems and human life, being the prolific source of animal proteins worldwide and a vertebrate model for biomedical research. We review miRNA biogenesis, regulation, modifications, and mechanisms of action. Specific sections are devoted to the role of miRNA in teleost development, organogenesis, tissue differentiation, growth, regeneration, reproduction, endocrine system, and responses to environmental stimuli. Each section discusses gaps in the current knowledge and pinpoints the future directions of research on miRNA in teleosts.

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microRNA in teleost fish

Steroids in teleost fishes: A functional point of view

Next-generation sequencing experiments have shown that microRNAs (miRNAs) are expressed in many different isoforms (isomiRs), whose biological relevance is often unclear We found that mature miR-21, the most widely researched miRNA because of its importance in human disease, is produced in two prevalent isomiR forms that differ by 1 nt at their 3' end, and moreover that the 3' end of miR-21 is posttranscriptionally adenylated by the noncanonical poly(A) polymerase PAPD5 PAPD5 knockdown caused an increase in the miR-21 expression level, suggesting that PAPD5-mediated adenylation of miR-21 leads to its degradation Exoribonuclease knockdown experiments followed by small-RNA sequencing suggested that PARN degrades miR-21 in the 3'-to-5' direction In accordance with this model, microarray expression profiling demonstrated that PAPD5 knockdown results in a down-regulation of miR-21 target mRNAs We found that disruption of the miR-21 adenylation and degradation pathway is a general feature in tumors across a wide range of tissues, as evidenced by data from The Cancer Genome Atlas, as well as in the noncancerous proliferative disease psoriasis We conclude that PAPD5 and PARN mediate degradation of oncogenic miRNA miR-21 through a tailing and trimming process, and that this pathway is disrupted in cancer and other proliferative diseases

https://www.pnas.org/content/pnas/111/31/11467.full.pdf

PAPD5-mediated 3′ adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease

Background: MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs of 20–25 nucleotides that play a key role in diverse biological processes. Japanese flounder undergo dramatic metamorphosis in their early development. The metamorphosis is characterized by morphological transformation from a bilaterally symmetrical to an asymmetrical body shape concomitant with extensive morphological and physiological remodeling of organs. So far, only a few miRNAs have been identified in fish and there are very few reports about the Japanese flounder miRNA. Methodology/Principal Findings: Solexa sequencing technology was used to perform high throughput sequencing of the small RNA library from the metamorphic period of Japanese flounder. Subsequently, aligning these sequencing data with metazoan known miRNAs, we characterized 140 conserved miRNAs and 57 miRNA: miRNA* pairs from the small RNA library. Among these 57 miRNA: miRNA* pairs, twenty flounder miRNA precursors were amplified from genomic DNA. We also demonstrated evolutionary conservation of Japanese flounder miRNAs and miRNA* in the animal evolution process. Using miRNA microarrays, we identified 66 differentially expressed miRNAs at two metamorphic stages (17 and 29 days post hatching) of Japanese flounder. The results show that miRNAs might play a key role in regulating gene expression during Japanese flounder metamorphosis. Conclusions/Significance: We identified a large number of miRNAs during flounder metamorphosis, some of which are differentially expressed at two different metamorphic stages. The study provides an opportunity for further understanding of miRNA function in the regulation of flounder metamorphosis and gives us clues for further studies of the mechanisms of metamorphosis in Japanese flounder.

/pdf/identification-and-differential-expression-of-micrornas-2ufqp6zc1w.pdf

Identification and differential expression of microRNAs during metamorphosis of the Japanese flounder (Paralichthys olivaceus).

MiR-1, miR-133a, and miR-206a have been identified as muscle-specific miRNAs. They play multiple crucial roles in the regulation of muscle development. Here, we show that these miRNAs were differentially expressed during the larval development of flounder, and specifically expressed in skeletal muscle and heart in adult tissues/organs. The expression levels of these miRNAs were significantly changed by thyroid hormone (TH) or thiourea (TU) treatment during metamorphosis from 17 dph (days post hatching) to 42 dph. In addition, the expression levels of MyoD and Myf5 mRNAs markedly increased at 14 dph (pre-metamorphosis) compared to metamorphic stages, and their expression levels are far above the myogenin during larval development. Moreover, these MRFs (myogenic regulatory factors) expression were directly or indirectly regulated by thyroid hormone or thiourea during metamorphosis. All the results suggest that miRNAs and MRFs might be involved in signaling pathway of TH or TU-mediated flounder metamorphosis.

Expression and regulation of miR-1, -133a, -206a, and MRFs by thyroid hormone during larval development in Paralichthys olivaceus.

The let-7 microRNAs (miRNAs), a class of small noncoding RNAs, are phylogenetically conserved and temporally expressed and control the proper timing of events during development as heterochronic genes in many animals. Japanese flounder (Paralichthys olivaceus) undergoes a metamorphosis from the larval to juvenile form. Here, we identified 21 let-7 miRNA precursors from different genome loci in Japanese flounder. P. olivaceus let-7 miRNAs are widely expressed in adult tissues, highly expressed during metamorphosis, but weakly during embryonic development. Exogenous thyroid hormone (0.1 mg/L), which induces premature metamorphosis, significantly promotes the expression of let-7 miRNAs, while thiourea (30 mg/L), which affects metamorphic arrest, inhibits the expression of let-7 miRNAs in metamorphosis in P. olivaceus. These results show that let-7 miRNAs widely participate in tissue development and metabolism during development and are also involved in regulation of temporal transitions associated with cell proliferation and differentiation during metamorphosis, in P. olivaceus.

Expression of let-7 microRNAs that are involved in Japanese flounder (Paralichthys olivaceus) metamorphosis.

Histone deacetylase 4, which is a class II histone deacetylase, plays a critical role in development, differentiation of muscle, cell proliferation and metabolism. In our study, we obtained the full-length HDAC4 cDNA, which included the coding region of 3171bp, a 180bp 5'untranslated region (UTR) and a 760bp 3'UTR. The deduced HDAC4 protein contained all known functional domains identified in other organisms. The phylogenetic analysis indicated that Paralichthys olivaceus HDAC4 had the highest identity with the Takifugu rubripes. Tissue distribution analysis indicated that HDAC4 is abundantly expressed in muscle, and its levels are significantly higher in muscle than in other tissues (P<0.01). HDAC4 mRNA levels at 3dph (days post hatching) and 36dph were higher than that in other stages. Exogenous thyroid hormones either directly or indirectly promoted the expression of HDAC4 mRNA during metamorphosis, indicating that HDAC4 might directly or indirectly be regulated by thyroid hormone during muscle development in metamorphosis. To identify the miRNAs targeting HDAC4, we performed a luciferase reporter assay and verified that HDAC4 is a common target gene of miR-1 and miR-133a indicating that HDAC4 might be involved in a signal pathway of microRNA regulating muscle development.

Zhiyi Shi

Papers

Identification and differential expression of microRNAs during metamorphosis of the Japanese flounder (Paralichthys olivaceus).

Expression and regulation of miR-1, -133a, -206a, and MRFs by thyroid hormone during larval development in Paralichthys olivaceus.

Expression of let-7 microRNAs that are involved in Japanese flounder (Paralichthys olivaceus) metamorphosis.

Identification and expression of HDAC4 targeted by miR-1 and miR-133a during early development in Paralichthys olivaceus

Identification and expression of the target gene emx2 of miR-26a and miR-26b in Paralichthys olivaceus.