DNA methylation directs microRNA biogenesis in mammalian cells

Glaich, Ohad; Parikh, Shivang; Bell, Rachel E.; Mekahel, Keren; Donyo, Maya; Leader, Yodfat; Shayevitch, Ronna; Sheinboim, Danna; Yannai, Sivan; Hollander, Dror; Melamed, Ze’ev; Lev-Maor, Galit; Ast, Gil; Levy, Carmit

doi:10.1038/s41467-019-13527-1

Cited by 89 publications

(59 citation statements)

References 83 publications

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“…Similarly, re-expression of miRNAs in response to DIM was demonstrated in cancer cell lines [44]. According to Glaich et al [45], miRNAs encoded by highly methylated loci are more frequently expressed than miRNAs which are encoded by unmethylated loci. We suggest that in sham animals, DIM-evoked hypomethylation of global DNA could account for low expression of miRNAs, except for miRNAs, which control apoptosis, autophagy and/or excitotoxicity and inhibit the vulnerability of cerebral tissue to ischemic injury.…”

Section: Discussionmentioning

confidence: 95%

Neuroprotective effect of 3,3’-Diindolylmethane against perinatal asphyxia involves inhibition of the AhR and NMDA signaling and hypermethylation of specific genes

et al. 2020

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Each year, 1 million children die due to perinatal asphyxia; however, there are no effective drugs to protect the neonatal brain against hypoxic/ischemic damage. In this study, we demonstrated for the first time the neuroprotective capacity of 3,3’-diindolylmethane (DIM) in an in vivo model of rat perinatal asphyxia, which has translational value and corresponds to hypoxic/ischemic episodes in human newborns. Posttreatment with DIM restored the weight of the ipsilateral hemisphere and normalized cell number in the brain structures of rats exposed to perinatal asphyxia. DIM also downregulated the mRNA expression of HIF1A-regulated Bnip3 and Hif1a which is a hypoxic marker, and the expression of miR-181b which is an indicator of perinatal asphyxia. In addition, DIM inhibited apoptosis and oxidative stress accompanying perinatal asphyxia through: downregulation of FAS, CASP-3, CAPN1, GPx3 and SOD-1, attenuation of caspase-9 activity, and upregulation of anti-apoptotic Bcl2 mRNA. The protective effects of DIM were accompanied by the inhibition of the AhR and NMDA signaling pathways, as indicated by the reduced expression levels of AhR, ARNT, CYP1A1, GluN1 and GluN2B, which was correlated with enhanced global DNA methylation and the methylation of the Ahr and Grin2b genes. Because our study provided evidence that in rat brain undergoing perinatal asphyxia, DIM predominantly targets AhR and NMDA, we postulate that compounds that possess the ability to inhibit their signaling are promising therapeutic tools to prevent stroke.

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Section: Discussionmentioning

confidence: 95%

Neuroprotective effect of 3,3’-Diindolylmethane against perinatal asphyxia involves inhibition of the AhR and NMDA signaling and hypermethylation of specific genes

et al. 2020

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“…SETDB1 levels are greatly increased in numerous cancers, including lung cancer (Lafuente-Sanchis et al, 2016;Chen B. et al, 2018), and is an important epigenetic regulator involved in control of histone methylation in tumorigenesis, dysregulation of histone methylation, and aberrant miRNA profiling, contributing to tumorigenesis and progression (Chen Y. et al, 2018;Michalak et al, 2019). Moreover, DNA methylation can directly influence miRNA biogenesis (Glaich et al, 2019). Numerous microRNAs can be epigenetically silenced by DNA methylation of their promotor regions.…”

Section: Discussionmentioning

confidence: 99%

SOD1 Promotes Cell Proliferation and Metastasis in Non-small Cell Lung Cancer via an miR-409-3p/SOD1/SETDB1 Epigenetic Regulatory Feedforward Loop

Liu

et al. 2020

Front. Cell Dev. Biol.

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Superoxide dismutase 1(SOD1) is a major antioxidant with oncogenic effects in many human cancers. Although SOD1 is overexpressed in various cancers, the clinical significance and functions of SOD1 in non-small cell lung cancer (NSCLC), particularly the epigenetic regulation of SOD1 in NSCLC carcinogenesis and progression have been less well investigated. In this study, we found that SOD1 expression was upregulated in NSCLC cell lines and tissues. Further, elevated SOD1 expression could promote NSCLC cell proliferation, invasion and migration. While inhibition of SOD1 expression induced NSCLC G1-phase cell cycle arrest and promoted apoptosis. In addition, miR-409-3p could repress SOD1 expression and significantly counteract its oncogenic activities. Bioinformatics analysis indicated that SET domain bifurcated histone lysine methyltransferase1 (SETDB1) was involved in the epigenetic regulation of miR-409-3p and SOD1 expression and functions in NSCLC cells. Identification of this miR-409-3p/SOD1/SETDB1 epigenetic regulatory feedforward loop may provide new insights into further understanding of NSCLC tumorigenesis and progression. Additionally, our results incicate that SOD1 may be a potential new therapeutic target for NSCLC treatment.

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“…The last pathway is from DNA methylation to protein via miRNAs. This dependence is primarily based on recent studies that have shown the influence of DNA methylation directly on the expression of miRNAs [ 44 ]. Note that these relationships are not exhaustive and additional experiments will be needed to fully model the pathways that influence the production of protein from DNA.…”

Section: Resultsmentioning

confidence: 99%

Directionally dependent multi-view clustering using copula model

et al. 2020

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Recent developments in high-throughput methods have resulted in the collection of high-dimensional data types from multiple sources and technologies that measure distinct yet complementary information. Integrated clustering of such multiple data types or multi-view clustering is critical for revealing pathological insights. However, multi-view clustering is challenging due to the complex dependence structure between multiple data types, including directional dependency. Specifically, genomics data types have pre-specified directional dependencies known as the central dogma that describes the process of information flow from DNA to messenger RNA (mRNA) and then from mRNA to protein. Most of the existing multi-view clustering approaches assume an independent structure or pair-wise (non-directional) dependence between data types, thereby ignoring their directional relationship. Motivated by this, we propose a biology-inspired Bayesian integrated multi-view clustering model that uses an asymmetric copula to accommodate the directional dependencies between the data types. Via extensive simulation experiments, we demonstrate the negative impact of ignoring directional dependency on clustering performance. We also present an application of our model to a real-world dataset of breast cancer tumor samples collected from The Cancer Genome Altas program and provide comparative results.

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DNA methylation directs microRNA biogenesis in mammalian cells

Cited by 89 publications

References 83 publications

Neuroprotective effect of 3,3’-Diindolylmethane against perinatal asphyxia involves inhibition of the AhR and NMDA signaling and hypermethylation of specific genes

Neuroprotective effect of 3,3’-Diindolylmethane against perinatal asphyxia involves inhibition of the AhR and NMDA signaling and hypermethylation of specific genes

SOD1 Promotes Cell Proliferation and Metastasis in Non-small Cell Lung Cancer via an miR-409-3p/SOD1/SETDB1 Epigenetic Regulatory Feedforward Loop

Directionally dependent multi-view clustering using copula model

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