Focus on the Progress of miRNA Research Made by Scientists in Recent Years (Ⅰ)

Focus on the Progress of miRNA Research Made by Scientists in Recent Years (Ⅰ)

The study revealed a new mechanism of microRNA inhibiting mRNA expression

Each miRNA associates with an Argonaute (AGO) protein to form a silencing complex, in which the miRNA is paired with sites within target transcripts and the AGO protein promotes destabilization and/or translational repression of bound target. The success rate with which a miRNA is able to repress a specific gene is called its targeting efficacy, and researchers have used various models to calculate it, with mixed results. Although a variety of approaches have provided insight into target recognition, the sparsity of miRNA–target affinity measurements has limited understanding and prediction of targeting efficacy. However, in a new study, scientists from the Whitehead Institute for Biomedical Research collected a massive amount of data on six miRNAs, and from that foundation developed an improved predictive model for all individual miRNAs. Their findings provide unprecedented accuracy and granularity for miRNA target prediction, and the related research results were recently published in the journal Science.

Researchers adapted RNA bind-n-seq to measure the relative binding affinities between Argonaute-miRNA complexes and all ≤12-nucleotide sequences. This approach revealed noncanonical target sites unique to each miRNA, miRNA-specific differences in canonical target-site affinities, and a 100-fold impact of dinucleotides flanking each site. These data enabled the construction of a biochemical model of miRNA-mediated repression, which was extended to all miRNA sequences through a convolutional neural network. The new level of specificity in miRNA targeting prediction will provide all researchers working on the subject with better information about the impact of a given miRNA in a cell.

Reference

  1. McGeary S E, et al. The biochemical basis of microRNA targeting efficacy. Science, 2019, 366(6472).

microRNA molecules may link the immune system to brain cells

Recently, a number of studies have found that schizophrenia or bipolar disorder have a high genetic similarity. The disease-specific changes in brain cells of schizophrenia and bipolar disorder overlap more than 70%, and these changes will affect gene expression. In a study published in the international journal Cell Reports, scientists from the Goethe University and the Hebrew University of Jerusalem revealed the differences between afflicted men and women and identifies disease-affected pathways of cholinergic transmission and gp130-family neurokine controllers of immune function linked by microRNAs.

RNA sequencing analyses are usually limited to identifying lowest p value transcripts, which does not involve polygenic phenomena. To overcome this limitation, researchers have developed an integrative approach that combines large-scale transcriptomic meta-analysis of patient brain tissues with single-cell sequencing data of neurons in the central nervous system, short RNA sequencing of human male- and female-originating cell lines, and connectomics of the interaction of transcription factors and microRNAs with interfering transcripts. The method identified 3 miRNA families associated with both diseases and 5 associated with schizophrenia, but none of them was associated with bipolar disorder alone, retracing the increased severity from a non-coding perspective. Besides, the method also reveals the differences between afflicted men and women and identifies disease-affected pathways of cholinergic transmission and gp130-family neurokine controllers of immune function interlinked by microRNAs. This method may open up a new prospect for finding biomarkers and therapeutic targets in other transmitter systems and diseases.

Focus on the Progress of miRNA Research Made by Scientists in Recent Years (Ⅰ)

Reference

  1. Lobentanzer S, et al. Integrative Transcriptomics reveals sexually dimorphic control of the cholinergic/Neurokine Interface in schizophrenia and bipolar disorder. Cell Reports, 2019, 29(3): 764-777. e5.

Insufficient sleep can affect the microRNA function, and then damage cardiovascular

Habitual insufficient nightly sleep, defined as less than 7 h night−1, is associated with increased cardiovascular disease (CVD) risk, events and mortality. However, the mechanisms underlying the detrimental cardiovascular effects of habitual short sleep duration are not fully understood. In a study published in the international journal Experimental Physiology, scientists from the University of Colorado found that individuals who habitually sleep less than 7 h night−1 have lower levels of three physiological modulators (miRNAs), which can affect gene expression and play a key role in maintaining vascular health.

miRNAs are short non-coding RNAs that regulate gene expression at the post-transcriptional level by targeting mRNA and inhibiting translation. A specific subset of miRNAs is considered to be important regulators of vascular inflammation, endothelial cell dysfunction and vasoconstrictor tone. For instance, inhibition of miR-92a and overexpression of miR-146a, miR-181b and miR-Let-7a are associated with suppressed endothelial inflammation and atherogenesis. Both miR-145 and miR-150 limit the activation of immune cells, the production of cytokines and vascular inflammation. However, it is not clear whether habitual short sleep is associated with altered circulating miRNA expression. Circulating miRNA desynchrony may contribute to the increased cardiovascular risk associated with short sleep. In this study, researchers determine the influence of habitual short sleep on a subset of specific vascular-related miRNAs. These data suggested that chronic short sleep is associated with a marked reduction in circulating levels of miR-125a, miR-126 and miR-146a. Dysregulation of these miRNAs may lead to the increased inflammatory burden and endothelial dysfunction associated with habitual insufficient sleep.

Reference

  1. Hijmans J G, et al. Insufficient sleep is associated with a pro-atherogenic circulating microRNA signature. Experimental physiology, 2019, 104(6): 975-982.

Targeting miRNA processing is expected to develop new anticancer therapies

Melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24) is a multifunctional cytokine, which shows broad-spectrum anticancer activity in preclinical animal cancer models and in a phase 1/2 clinical trial in patients with advanced cancers. In a study published in the international journal Proceedings of the National Academy of Sciences, scientists from Virginia Commonwealth University revealed how MDA-7/IL-24 genes drive cancer progression by influencing the function of microRNAs. In addition to being very important for cancer research, the related research results are also expected to help study the molecular mechanism of cardiovascular disease and neurodegenerative disease driven by the same microRNA.

Focus on the Progress of miRNA Research Made by Scientists in Recent Years (Ⅰ)

Cytoplasmic processing by DICER and downstream modifications of miRNAs are key regulators of miRNA biogenesis. The researchers demonstrated that MDA-7/IL-24, administered via a replication incompetent type 5 adenovirus (Ad.mda-7) or with His-MDA-7/IL-24 protein, down-regulates DICER, a crucial regulator in miRNA processing. DICER is unchanged by Ad.mda-7/IL-24 in normal immortal prostate cells, whereas Ad.mda-7 down-regulates DICER in multiple cancer cells including glioblastoma multiforme and breast, lung, prostate, and liver carcinoma cells. MDA-7/IL-24 protein down-regulates DICER expression through typical IL-20/IL-22 receptors. Stable overexpression of DICER in cancer cells impedes Ad.mda-7 or His-MDA-7/IL-24 inhibition of cell growth, colony formation, and apoptosis. Overexpression of DICER partially rescues MDA-7/IL-24-mediated cell death in cancer cells. In addition, MDA-7/IL-24-mediated DICER deregulation occurs through regulation of melanogenesis-associated transcription factor (MITF). These studies confirm a functional link between MDA-7/IL-24 and specific miR regulation and indicate that this pathway is enabled by a complex loop consisting of MITF and DICER. These findings provide targets for potentially enhancing anticancer activity of the therapeutic cytokine MDA-7/IL-24.

Reference

  1. Pradhan A K, et al. MDA-7/IL-24 regulates the miRNA processing enzyme DICER through downregulation of MITF. Proceedings of the National Academy of Sciences, 2019, 116(12): 5687-5692.

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