MicroRNAs (miRNAs) are short non-coding RNAs that act as important regulators of gene expression as part of the epigenetic machinery. In addition to posttranscriptional gene silencing by miRNAs, the epigenetic mechanisms also include DNA methylation, histone modifications and their crosstalk. Epigenetic modifications were reported to play an important role in many disease onsets and progressions and can be used to explain several features of complex diseases, such as late onset and fluctuation of symptoms. However, miRNAs not only function as a part of epigenetic machinery, but are also epigenetically modified by DNA methylation and histone modification like any other protein-coding gene. There is a strong connection between epigenome and miRNome, and any dysregulation of this complex system can result in various physiological and pathological conditions. In addition, miRNAs play an important role in toxicogenomics and may explain the relationship between toxicant exposure and tumorigenesis. The present review provides information on 63 miRNA genes shown to be epigenetically regulated in association with 21 diseases, including 11 cancer types: cardiac fibrosis, cardiovascular disease, preeclampsia, Hirschsprung’s disease, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, temporal lobe epilepsy, autism, pulmonary fibrosis, melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal, gastric, cervical, ovarian, prostate, lung, breast, and bladder cancer. The review revealed that hsa-miR-34a, hsa-miR-34b, and hsa-miR-34c are the most frequently reported epigenetically dysregulated miRNAs. There is a need to further study molecular mechanisms of various diseases to better understand the crosstalk between epigenetics and gene expression and to develop new therapeutic options and biomarkers.
Cancer DNA methylation Epigenetics Histone modification MicroRNA (miRNA) Toxicology
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We thank Tasha Murgel for critical reading of our manuscript.
This study was funded by the Slovenian Research Agency (ARRS) through the Research Program Comparative genomics and genome biodiversity (Grant Number P4-0220).
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Conflict of interest
The authors declare that they have no conflict of interest.
Ando T et al (2009) DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: its possible involvement in the formation of epigenetic field defect. Int J Cancer 124:2367–2374. doi:10.1002/ijc.24219CrossRefPubMedGoogle Scholar
Blümcke I et al (2013) International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia 54:1315–1329. doi:10.1111/epi.12220CrossRefPubMedGoogle Scholar
Chen KC, Liao YC, Hsieh IC, Wang YS, Hu CY, Juo SH (2012) OxLDL causes both epigenetic modification and signaling regulation on the microRNA-29b gene: novel mechanisms for cardiovascular diseases. J Mol Cell Cardiol 52:587–595. doi:10.1016/j.yjmcc.2011.12.005CrossRefPubMedGoogle Scholar
Cordero F et al (2015) Differentially methylated microRNAs in prediagnostic samples of subjects who developed breast cancer in the European Prospective Investigation into Nutrition and Cancer (EPIC-Italy) cohort. Carcinogenesis 36:1144–1153. doi:10.1093/carcin/bgv102CrossRefPubMedGoogle Scholar
Ding S et al (2012) Decreased microRNA-142-3p/5p expression causes CD4+ T cell activation and B cell hyperstimulation in systemic lupus erythematosus. Arthritis Rheum 64:2953–2963. doi:10.1002/art.34505CrossRefPubMedGoogle Scholar
Doridot L, Houry D, Gaillard H, Chelbi ST, Barbaux S, Vaiman D (2014) miR-34a expression, epigenetic regulation, and function in human placental diseases. Epigenetics 9:142–151. doi:10.4161/epi.26196CrossRefPubMedGoogle Scholar
Kibbe WA et al (2015) Disease ontology 2015 update: an expanded and updated database of human diseases for linking biomedical knowledge through disease data. Nucleic Acids Res 43:D1071–D1078. doi:10.1093/nar/gku1011CrossRefPubMedGoogle Scholar
Saito Y, Liang G, Egger G, Friedman JM, Chuang JC, Coetzee GA, Jones PA (2006) Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 9:435–443. doi:10.1016/j.ccr.2006.04.020CrossRefPubMedGoogle Scholar
Strmsek Z, Kunej T (2014) Data integration of 104 studies related with microRNA epigenetics revealed that miR-34 gene family is silenced by DNA methylation in the highest number of cancer types. doi:10.15190/d.2014.10Google Scholar
Tanaka T et al (2011) Epigenetic silencing of microRNA-373 plays an important role in regulating cell proliferation in colon cancer. Oncol Rep 26:1329–1335. doi:10.3892/or.2011.1401PubMedGoogle Scholar
Vogt M et al (2011) Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas. Virchows Arch 458:313–322. doi:10.1007/s00428-010-1030-5CrossRefPubMedGoogle Scholar
Wang B et al (2016) Epigenetic silencing of microRNA-218 via EZH2-mediated H3K27 trimethylation is involved in malignant transformation of HBE cells induced by cigarette smoke extract. Arch Toxicol 90:449–461. doi:10.1007/s00204-014-1435-zCrossRefPubMedGoogle Scholar
Zhao S et al (2011) MicroRNA-126 regulates DNA methylation in CD4+ T cells and contributes to systemic lupus erythematosus by targeting DNA methyltransferase 1. Arthritis Rheum 63:1376–1386. doi:10.1002/art.30196CrossRefPubMedGoogle Scholar