Regulation of microRNAs in cancer metastasis

Metastasis is a phenomenon of crucial importance in defining prognosis in patients with cancer and is often responsible for cancer-related mortality. It is known that several steps are necessary for clonal cells to disseminate from their primary tumor site and colonize distant tissues, thus originating metastatic lesions. Therefore, investigating the molecular actors regulating this process may provide helpful insights in the development of efficient therapeutic responses. Recent evidences have indicated the role of microRNAs (miRNAs) in modulating the metastatic process in solid tumors. miRNAs are small regulatory non-coding RNAs that bind to specific target mRNAs, leading to translational repression. miRNAs are known to act as negative regulators of gene expression and are involved in the regulation of biological processes, including cell growth, differentiation and apoptosis, both in physiological conditions and during diseases, such as tumors. In the specific field of tumorigenesis, miRNAs play an important role in mediating oncogenesis and favoring tumor progression, as a result of their ability to modulate epithelial-to-mesenchymal transition (EMT) and other series of events facilitating the formation of metastasis. The role of miRNAs in cancer development has been widely studied and has helped elucidate events such as the change in expression of oncogenes, tumor-suppressors and cancer-related proteins. This review focuses on the mechanisms underlying the role of miRNAs as part of the metastatic process.     

Environmental chemicals and microRNAs

MicroRNAs (miRNAs) are short single-stranded non-coding molecules that function as negative regulators to silence or suppress gene expression. Aberrant miRNA expression has been implicated in a several cellular processes and pathogenic pathways of a number of diseases. Evidence is rapidly growing that miRNA regulation of gene expression may be affected by environmental chemicals. These environmental exposures include those that have frequently been associated with chronic diseases, such as heavy metals, air pollution, bisphenol A, and cigarette smoking. In this article, we review the published data on miRNAs in relation to the exposure to several environmental chemicals, and discuss the potential mechanisms that may link environmental chemicals to miRNA alterations. We further discuss the challenges in environmental-miRNA research and possible future directions. The accumulating evidence linking miRNAs to environmental chemicals, coupled with the unique regulatory role of miRNAs in gene expression, makes miRNAs potential biomarkers for better understanding the mechanisms of environmental diseases.     

CpG Island Hypermethylation of Tumor Suppressor microRNAs in Human Cancer

In the last few years, microRNAs have started a revolution in molecular biology and emerged as key players in the cancer process. For these reasons, it is extremely important to understand the physiological and disease-associated mechanisms underlying the regulation of these small, single-stranded RNAs. Thus, it was merely a matter of time before microRNAs and epigenetics coincided. In cancer, aberrant DNA hypermethylation of tumor suppressor genes, global genomic DNA hypomethylation, and disruption of the histone modification patterns are the main epigenetic alterations, and have consequently been widely studied. Some microRNAs are downregulated in cancer and act as bona fide tumor suppressor genes, and this knowledge led to the proposal of the hypothesis that miRNAs could be silenced by epigenetic mechanisms. It has recently been shown that miR-127 and miR-124a, two putative tumor suppressor miRNAs, are methylated in tumor cells. Epigenomic tools can be effectively used in the search for new methylated tumor suppressor microRNAs. Furthermore, this aberrant methylation can be reversed by epigenetic drugs, such as DNA demethylating agents and histone deacetylase inhibitors, restoring microRNA expression levels and reverting the tumoral phenotype. In the coming years we will come to realize more fully the relevance of this expected encounter between two forces – epigenetics and microRNAs – that are currently at the forefront of biology.     

miRNA在植物重金属胁迫应答中的作用

microRNA （miRNA）是一种新型的长度为20~24 nt的非编码RNA,通过对靶基因的表达调节进而参与调控植物体的多种生理代谢活动。重金属是一类重要的环境污染物,严重危害植物的生长发育,甚至导致植物死亡。植物在长期的进化过程中形成了抵御重金属胁迫的多种机制,如miRNA对特定基因转录后水平的调控就在逆境胁迫应答中发挥重要作用。本文综述了植物中参与重金属胁迫应答miRNA的种类及作用机制,为揭示重金属胁迫条件下基因表达调控机制,以及利用基因工程手段改良植物对重金属的耐受性提供了线索和依据。     

Epigenetics in Ocular Diseases

Epigenetics pertains to heritable alterations in gene expression that do not involve modification of the underlying genomic DNA sequence. Historically, the study of epigenetic mechanisms has focused on DNA methylation and histone modifications, but the concept of epigenetics has been more recently extended to include microRNAs as well. Epigenetic patterning is modified by environmental exposures and may be a mechanistic link between environmental risk factors and the development of disease. Epigenetic dysregulation has been associated with a variety of human diseases, including cancer, neurological disorders, and autoimmune diseases. In this review, we consider the role of epigenetics in common ocular diseases, with a particular focus on DNA methylation and microRNAs. DNA methylation is a critical regulator of gene expression in the eye and is necessary for the proper development and postmitotic survival of retinal neurons. Aberrant methylation patterns have been associated with age-related macular degeneration, susceptibility to oxidative stress, cataract, pterygium, and retinoblastoma. Changes in histone modifications have also been observed in experimental models of diabetic retinopathy and glaucoma. The expression levels of specific microRNAs have also been found to be altered in the context of ocular inflammation, retinal degeneration, pathological angiogenesis, diabetic retinopathy, and ocular neoplasms. Although the complete spectrum of epigenetic modifications remains to be more fully explored, it is clear that epigenetic dysregulation is an important contributor to common ocular diseases and may be a relevant therapeutic target.     

An integrative approach to identify hexaploid wheat miRNAome associated with development and tolerance to abiotic stress

Background

Wheat is a major staple crop with broad adaptability to a wide range of environmental conditions. This adaptability involves several stress and developmentally responsive genes, in which microRNAs (miRNAs) have emerged as important regulatory factors. However, the currently used approaches to identify miRNAs in this polyploid complex system focus on conserved and highly expressed miRNAs avoiding regularly those that are often lineage-specific, condition-specific, or appeared recently in evolution. In addition, many environmental and biological factors affecting miRNA expression were not yet considered, resulting still in an incomplete repertoire of wheat miRNAs.

Results

We developed a conservation-independent technique based on an integrative approach that combines machine learning, bioinformatic tools, biological insights of known miRNA expression profiles and universal criteria of plant miRNAs to identify miRNAs with more confidence. The developed pipeline can potentially identify novel wheat miRNAs that share features common to several species or that are species specific or clade specific. It allowed the discovery of 199 miRNA candidates associated with different abiotic stresses and development stages. We also highlight from the raw data 267 miRNAs conserved with 43 miRBase families. The predicted miRNAs are highly associated with abiotic stress responses, tolerance and development. GO enrichment analysis showed that they may play biological and physiological roles associated with cold, salt and aluminum (Al) through auxin signaling pathways, regulation of gene expression, ubiquitination, transport, carbohydrates, gibberellins, lipid, glutathione and secondary metabolism, photosynthesis, as well as floral transition and flowering.

Conclusion

This approach provides a broad repertoire of hexaploid wheat miRNAs associated with abiotic stress responses, tolerance and development. These valuable resources of expressed wheat miRNAs will help in elucidating the regulatory mechanisms involved in freezing and Al responses and tolerance mechanisms as well as for development and flowering. In the long term, it may help in breeding stress tolerant plants.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1490-8) contains supplementary material, which is available to authorized users.     

microRNA的调控和被调控

microRNA是一大类长度约22 nt的非编码RNA,可与靶基因的3′-UTR区部分或完全配对结合,进而通过降低靶mRNA的稳定性或抑制翻译而下调目的基因的表达. microRNA不仅参与细胞的增殖、分化、死亡等正常生理过程,而且还与包括癌症在内的诸多病理过程密切相关.microRNA通常位于编码基因的内含子区,主要由RNA聚合酶Ⅱ催化而转录为初始microRNA,接着经过一系列的核内、胞浆内酶切步骤而组装成有功能的RNA诱导的沉默复合体.本文将在简要介绍microRNA生物合成和调控功能的基础上,重点综述microRNA被调控的研究进展,主要包括表观遗传学水平、转录水平、转录后水平和降解的调控.近年来的研究,逐步丰富甚至推翻了以往对microRNA的认识,体现了microRNA生物学的复杂性.可以预见,随着研究的深入,microRNA将在疾病的早期防治中发挥越来越重要的作用.     

MicroRNAs as biomarkers of harmful environmental and occupational exposures: a systematic review

Abstract

Environmental exposure is a growing public health burden associated with several negative health effects. An estimated 4.2 million deaths occur each year from ambient air pollution alone. Biomarkers that reflect specific exposures have the potential to measure the real integrated internal dose from all routes of complex environmental exposure. MicroRNAs (miRNAs), small non-coding RNAs that regulate gene expression, have been studied as biomarkers in various diseases and have also shown potential as environmental exposure biomarkers. Here, we review the available human epidemiological and experimental evidence of miRNA expression changes in response to specific environmental exposures including airborne particulate matter. In doing so, we establish that miRNA exposure biomarker development remains in its infancy and future studies will need to carefully consider biological and analytical ‘design rules’ in order to facilitate clinical translation.     

DNA甲基化与microRNA

细胞中DNA甲基化和microRNA（miRNA）相互影响,并共同调控着下游靶基因的表达活性,在细胞生长代谢、免疫、肿瘤和心血管疾病等生理和病理过程中发挥重要作用。首先简要介绍DNA甲基化与miRNA的概况,然后分析了miRNA调控下的DNA甲基化改变,探讨了DNA甲基化影响miRNA的表达活性变化,并归纳了miRNA与DNA甲基化之间的反馈调控关系;最后对DNA甲基化和miRNA的应用前景进行了简单探讨。研究DNA甲基化与miRNA间的网络调控关系,可为表观调控机制在理论和实践中的深入研究和应用提供参考。     

MicroRNA-mediated DNA methylation in plants

DNA methylation, a major event in epigenetics, plays an essential role in the control of gene expression. Increasing evidence suggests that long and short non-coding RNAs are involved extensively in plants to direct the establishment, spread, and removal of DNA cytosine methylation throughout their genomes. Yet, little has been known about the role of microRNAs (miRNAs) in DNA methylation although the role of small interfering RNAs (siRNAs) in DNA methylation has been well established. Several recent studies, however, provided the evidence for miRNA-directed DNA methylation in plants, and the working mechanisms still need to be fully explored. In this review, we highlight the key features of miRNA-directed DNA methylation in plants and provide insight into the complexities of such an event in plants. The interaction between miRNAs and the epigenetic machinery and the future potential research questions are briefly discussed.     

MicroRNA signature of air pollution exposure-induced congenital defects

Air pollution exposure has been increasing extensively and there are evidence suggesting that exposure to air pollution during pregnancy can lead to congenital defects in the offspring. Recent findings suggested that microRNAs (miRNAs) might play important roles in the pathogenesis of developmental defects. However, the miRNAs profile pattern in the air pollution-exposed embryos remains unknown. RNA sequencing was performed to determine the differentially expressed miRNAs in the rat embryos (gestation day 9) with or without air pollution exposure. The potential functions and the associated mechanisms of these differentially expressed miRNAs were determined using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analyses. The regulatory networks of mRNA–miRNA interactions were also reconstructed. As compared with the control group, a total of 291 miRNAs were differentially expressed in the rat embryos from the air pollution-exposed group, in which 204 and 87 miRNAs were significantly downregulated and upregulated, respectively. These miRNAs were predicted to deregulate mitotic spindle organization, cellular respiration, glycolate metabolism, and proteasome. Extensive regulation of target genes by miR-346, miR-504, miR-214-3p and miR-1224 was also predicted. Our results suggested that miRNAs may play crucial roles in the pathogenesis of air pollution-induced congenital spinal defects through deregulating multiple biological processes.