Implication of obesity-induced miR-96 in hepatic insulin resistance: DOI: 10.14800/rd.1615

Obesity is a serious health problem that is caused by an equilibrium shift towards elevated energy intake over expenditure, and is often involved in a range of metabolic diseases. A diet rich in saturated fatty acids (SFA), which is one of the leading causes of obesity and ectopic lipid accumulation in the key organs for metabolic regulation, results in an imbalance of the cellular metabolism and an inadequate response of hepatocytes to insulin, which is known as hepatic insulin resistance. Although endogenous non-coding small microRNAs (miRNAs) play important roles in the post-transcriptional repression of the target genes, the implications of obesity-induced miRNAs in metabolic diseases, particularly in the development of hepatic insulin resistance, are largely unknown. In recent studies, SFA and a high fat diet were found to increase the expression of certain miRNAs significantly in the liver and skeletal muscle. These obesity-induced miRNAs were also up-regulated in human subjects with metabolic diseases. Our recent study highlights a novel mechanism whereby miR-96, which is one of the obesity-induced miRNA, participates actively in the development of hepatic insulin resistance in obesity. Studies focusing on obesity-induced miR-96 have indicated the strong diagnostic and therapeutic importance of miRNAs in insulin resistance and metabolic diseases. This will also help better understand the pathogenesis of insulin resistance and T2DM in obesity, and enable the development of inhibitors against obesity-induced miRNAs as a novel diagnostic and therapeutic strategy for metabolic diseases

Non-coding RNA: From Bench to Bedside: DOI: 10.14800/rd.45

Since the Precision Medicine Initiative was launched in 2015, tremendous progress has been documented in this field [1]. Specifically, non-coding RNA (ncRNA) has been getting increased attention as it has been implicated in contributing to different diseases, including cancer [2]. ncRNAs are known to regulate gene expression at the transcriptional and post-transcriptional levels, influencing chromatin remodeling and signal transduction. Deregulation of ncRNAs has an impact on the impairment of physiological programs, driving cells in cancer development [2].  In recent years, ncRNAs have emerged as a previously unappreciated class of gene expression modulators that regulate various cellular processes, especially modulating gene expression in various cancers. Although most ncRNA research focuses on cancers, some scientists have been exploring their relationship to other diseases. For example, Lucafò M and colleagues found that ncRNA growth arrest-specific transcript 5 (GAS5) could mediate tissue damage in inflammatory bowel disease by modulating the expression of Matrix metalloproteinases (MMPs) [3]. Apart from that, the small molecule YK-4-279 blocks chimeric transcription factor EWS-FLI1 activity in Ewing sarcomas via inhibiting the expression of ncRNA Highly Upregulated in Liver Cancer (HULC), which help researchers to interpret the effect path of medicine [4]. Recent breakthroughs in genome engineering, such as CRISPR/Cas9 system, present a useful tool to advance ncRNA research [5, 6].  RNA-programmed genome editing using CRISPR/Cas9 is an ideal platform to genetically manipulate ncRNA molecules to mechanisti-cally and functionally dissect endogenous ncRNA networks in diseases. Efficiency in vivo delivery, however, has long been a major challenge as currently available lipid nanoparticles (LNPs) can induce liver damage and stimulate an immune response [7]. However, some new technologies seem to provide a better solution, such as LUNAR®-mediated delivery of RNA into cells developed by a commercial company, Arcturus Therapeutics in California [8]. Recent advances on ncRNA are likely to promote precision medicine, and results can be expected in the near future. However, before becoming accessible to patients, ncRNA has a long way to go

Bivalent aptamer-dual siRNA chimera is emerging as a new combination therapy: DOI: 10.14800/rd.1534

The selective delivery of siRNAs in a cell type-specific manner represents the major challenge for the application of RNA interference for disease treatment. Aptamers have great potentials as carriers for tumor specific siRNA delivery. With the nature of nucleic acid, aptamers can be ease of modification and editing. Novel bivalent aptamer-dual siRNA chimera (PSMA aptamer- survivin siRNA -EGFR siRNA -PSMA aptamer, PSEP) was developed by fusing two siRNAs (specific to EGFR and survivin) between two PSMA aptamers. Bivalent aptamer offers increased siRNA internalization compared with monovalent counterpart. PSEP chimera is able to inhibit EGFR and survivin simultaneously in a cell type-specific manner. In PSMA expressing tumor xenografts, PSEP significantly inhibits tumor growth and angiogenesis. Our results highlight that co-delivery of multiple siRNAs with bivalent aptamer represents a novel approach for targeting combination therapy

A novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in prostate cancer: DOI: 10.14800/rd.1503

Prostate cancer (PCa) is the second most common cause of cancer-specific deaths in the U.S. Unfortunately, the underlying molecular mechanisms for its development and progression remain unclear. Studies have established that microRNAs (miRNAs) are dysregulated in PCa. The intron-derived microRNA-1207-3p (miR-1207-3p) is encoded at the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, miR-1207-3p in PCa had not previously been investigated. Therefore, we explored if miR-1207-3p plays any regulatory role in PCa. We discovered that miR-1207-3p is significantly underexpressed in PCa cell lines in comparison to normal prostate epithelial cells, and that increased expression of microRNA-1207-3p in PCa cells significantly inhibits proliferation, migration, and induces apoptosis via direct molecular targeting of fibronectin type III domain containing 1 (FNDC1). Our studies also revealed significant overexpression of FNDC1, fibronectin (FN1) and the androgen receptor (AR) in human PCa cell lines as well as tissues, and FNDC1, FN1, and AR positively correlate with aggressive PCa. These findings, recently published in Experimental Cell Research, are the first to describe a novel miR-1207-3p/FNDC1/FN1/AR novel regulatory pathway in PCa

Technologies of high-throughput tissue-specific gene expression profiling: DOI: 10.14800/rd.1492

Gene expression profiling is an important strategy to study animal development, response to stimuli and diseases. RNAs measured in gene expression profiling experiments are frequently purified from mixture of multiple cell types. The resultant data have low resolution, incapable of distinguishing transcriptome of different cell types and likely biased towards up-regulated genes in dominant tissues. These problems can be solved by obtaining tissue-specific gene expression profile. For dozens of years, there have been several strategies developed to isolate specific tissues or purify RNAs from tissue of interest, and combined with high-throughput RNA assays to generate transcriptome of various specific tissues or cell types. This review will introduce basic principles of these methods and their application in large-scale transcriptome analysis, and discuss on their advantages and limitation

Links between mRNA splicing, mRNA quality control, and intellectual disability: DOI: 10.14800/rd.1448

In recent years, the impairment of RNA binding proteins that play key roles in the post-transcriptional regulation of gene expression has been linked to numerous neurological diseases. These RNA binding proteins perform critical mRNA processing steps in the nucleus, including splicing, polyadenylation, and export. In many cases, these RNA binding proteins are ubiquitously expressed raising key questions about why only brain function is impaired. Recently, mutations in the ZC3H14 gene, encoding an evolutionarily conserved, polyadenosine RNA binding protein, have been linked to a nonsyndromic form of autosomal recessive intellectual disability. Thus far, research on ZC3H14 and its Nab2 orthologs in budding yeast and Drosophila reveals that ZC3H14/Nab2 is important for mRNA processing and neuronal patterning. Two recent studies now provide evidence that ZC3H14/Nab2 may function in the quality control of mRNA splicing and export and could help to explain the molecular defects that cause neuronal dysfunction and lead to an inherited form of intellectual disability. These studies on ZC3H14/Nab2 reveal new clues to the puzzle of why loss of the ubiquitously expressed ZC3H14 protein specifically affects neurons

The miR-125a and miR-320c are potential tumor suppressor microRNAs epigenetically silenced by the polycomb repressive complex 2 in multiple myeloma: DOI: 10.14800/rd.1529

We have previously presented the histone methyltransferase enhancer of zeste homolog 2 (EZH2) of the polycomb repressive complex 2 (PRC2) as a potential therapeutic target in Multiple Myeloma (MM). In a recent article in Oncotarget by Alzrigat. et al. 2017, we have reported on the novel finding that EZH2 inhibition using the highly selective inhibitor of EZH2 enzymatic activity, UNC1999, reactivated the expression of microRNA genes previously reported to be underexpressed in MM. Among these, we have identified miR-125a-3p and miR-320c as potential tumor suppressor microRNAs as they were predicted to target MM-associated oncogenes; IRF-4, XBP-1 and BLIMP-1. We also found EZH2 inhibition to reactivate the expression of miR-494, a previously reported regulator of the c-MYC oncogene. In addition, we could report that EZH2 inhibition downregulated the expression of a few well described oncogenic microRNAs in MM. The data from our recent article are here highlighted as it shed a new light onto the oncogenic function of the PRC2 in MM. These data further strengthen the notion that the PRC2 complex may be of potential therapeutic interest

A possible link between specific transfer RNA methylation and tumorigenic phenotype of breast cancer: DOI: 10.14800/rd.1530

The human RNA methyltransferase BCDIN3D is overexpressed in breast cancer cells and involved in cellular invasion and poor prognosis of breast cancer. Several years ago, BCDIN3D was reported to dimethylate the 5\u27-monophosphate of specific precursor miRNAs (pre-miRNAs), such as the tumor suppressor miR145. Dimethylation of the 5\u27-monophosphate of the pre-miRNA negatively regulates the subsequent processing by Dicer in vitro, and results in the downregulated expression of the mature form of the miRNA. The depletion of BCDIN3D also reportedly results in the suppression of the tumorigenic phenotype of breast cancer cells. Thus, these findings suggested that BCDIN3D promotes the cellular invasion of breast cancer cells, by downregulating the expression of tumor suppressor miRNAs via the dimethylation of the 5\u27-monophosphate of the corresponding pre-miRNAs. Recently, we found that cytoplasmic tRNAHis is actually the primary target of human BCDIN3D, rather than pre-miR145. BCDIN3D monomethylates the 5\u27-phosphate of cytoplasmic tRNAHis much more efficiently than that of pre-miRNA in vitro, and is responsible for the monomethylation of the 5\u27-phosphate of cytoplasmic tRNAHisin vivo. BCDIN3D recognizes the eight-nucleotide long extended acceptor helix with the G-1-A73 mis-pair at the top of the acceptor stem of tRNAHis, which are exceptional features among cytoplasmic tRNA species. These results not only reveal the primary target of BCDIN3D, which is overexpressed in breast cancer cells, but also highlight the possible involvement of the 5\u27-phosphomethylation of tRNA and/or tRNA in the tumorigenesis of breast cancer cells, beyond its established function in protein synthesis

Emerging roles for miRNA-based post-transcriptional regulation in neuronal morphogenesis and neurodevelopmental disorders: DOI: 10.14800/rd.1456

Post-transcriptional regulation of gene expression is required for multiple aspects of neuronal development and function in the central nervous system. A sub-class of small non-coding RNA, called microRNAs (miRNAs), is emerging as key modulators of post-transcriptional gene regulation in numerous tissues, including the nervous system. Recent evidence has revealed a widespread role for miRNAs in various aspects of neuronal morphogenesis, including axogenesis, dendritogenesis, and synapse formation. Furthermore, dysregulation or altered expression of miRNAs has been associated with the pathogenesis of neurodevelopmental and psychiatric disorders. Here, we highlight recent advances in the study of miRNA-based regulation of neuronal development and their implications in neurological disorders

microRNA-29 mediates a novel negative feedback loop to regulate SCAP/SREBP-1 and lipid metabolism: DOI: 10.14800/rd.1525

The membrane-bound transcription factors, SREBPs (sterol regulatory element-binding proteins), play a central role in regulating lipid metabolism. The transcriptional activation of SREBPs requires the key protein SCAP (SREBP-cleavage activating protein) to translocate their precursors from the endoplasmic reticulum to the Golgi for subsequent proteolytic activation, a process tightly regulated by a cholesterol-mediated negative feedback loop. Our previous work showed that the SCAP/SREBP-1 pathway is significantly upregulated in human glioblastoma (GBM), the most deadly brain cancer, and that glucose-mediated N-glycosylation of SCAP is a prerequisite step for SCAP/SREBP trafficking. More recently, we demonstrated that microRNA-29 (miR-29) mediates a previously unrecognized negative feedback loop in SCAP/SREBP-1 signaling to control lipid metabolism. We found that SREBP-1, functioning as a transcription factor, promotes the expression of the miR-29 family members, miR-29a, -29b and -29c. In turn, the miR-29 isoforms reversely repress the expression of SCAP and SREBP-1. Moreover, treatment with miR-29 mimics effectively suppressed GBM tumor growth by inhibiting SCAP/SREBP-1 and de novo lipid synthesis. These findings, recently published in Cell Reports, strongly suggest that delivery of miR-29 in vivo may be a promising approach to treat cancer and metabolic diseases by suppressing SCAP/SREBP-1-regulated lipid metabolism