Genome-Wide Expression of MicroRNAs Is Regulated by DNA Methylation in Hepatocarcinogenesis

Shen, Jing; Wang, Shuang; Siegel, Abby B.; Remotti, Helen; Wang, Qiao; Sirosh, Iryna; Santella, Regina M.

doi:10.1155/2015/230642

Cited by 20 publications

(19 citation statements)

References 48 publications

(50 reference statements)

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“…Since promoter methylation and gene expression are usually inversely correlated, these results suggest DNA hypermethylation as a potential mechanism for the widespread downregulation of miRNA levels in FECD [36]. This preferential hypermethylation of miRNA gene promoters was also reported in other studies [33, 66-68].…”

Section: Discussionsupporting

confidence: 72%

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Pan

Weisenberger

Zheng

et al. 2019

Preprint

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18Homeostatic maintenance of corneal endothelial cells is essential for maintenance of corneal 19 deturgescence and corneal transparency. In Fuchs endothelial corneal dystrophy (FECD), an 20 accelerated loss and dysfunction of endothelial cells leads to progressively severe visual 21impairment. An abnormal accumulation of extracellular matrix is a distinctive hallmark of the 22 disease, however the molecular pathogenic mechanisms underlying this phenomenon are not fully 23 understood. We recently reported characteristic patterns of DNA methylation changes in the 24 corneal endothelial cells of patients with FECD. Here, we investigate genome-wide and sequence-25 specific DNA methylation changes of miRNA genes in corneal endothelial samples derived from 26 patients with FECD. We show that the majority of miRNA genes are hypermethylated at their 27 promoter regions in FECD. More specifically, miR-199B is an extensively hypermethylated 28 miRNA gene at its promoter region and its mature transcript miR-199b-5p was previously found 29 to be almost completely silenced in FECD. Using a cell-based assay, we find that miR-199b-5p 30 directly inhibits the expression of two epithelial mesenchymal transition (EMT)-inducing genes, 31Snai1 and ZEB1. Taken together, these findings suggest a novel regulatory mechanism of matrix 32 protein production by corneal endothelial cells in which miR-199b-5p hypermethylation leads to 33 its down-regulated expression and thereby the decreased expression of miR-199b-5p target genes, 34including Snai1 and ZEB1. Our results support miR-199b-5p as a potential therapeutic target to 35 prevent or slow down the progression of FECD disease. 36 37 Author summary 38 Fuchs endothelial corneal dystrophy (FECD) due to corneal endothelial cell degeneration is one 39 of the most common heritable causes of corneal visual loss and a leading indication for corneal 40 3 transplantation. The progressive loss of corneal endothelial cells is accompanied by an abnormal 41 deposition of extracellular matrix in the form of guttae. Here we discover that miRNA gene 42 promoters are frequent targets of aberrant DNA methylation in FECD. In particular, we describe 43 a novel epigenetic mechanism used by corneal endothelial cells to regulate extracellular matrix 44 production. We find that miRNA-199b-5p functions as a negative regulator of Snai1 and ZEB1, 45 two zinc finger transcription factors that have been shown to lead to increased production of 46 extracellular matrix proteins. Furthermore, miR-199B was extensively hypermethylated in FECD 47 and its mature transcript miR-199b-5p directly binds to the 3′-UTRs of Snai1 and ZEB1 genes. 48Ultimately, this may negatively modulate Snai1-and ZEB1-mediated production of extracellular 49 matrix proteins. This work is the first to identify an important role of DNA methylation in the 50 epigenetic regulation of miRNA-target genes in FECD and to describe a potential epigenetic 51 biomarker for the treatment of FECD patients. 52 53

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Section: Discussionsupporting

confidence: 72%

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Pan

Weisenberger

Zheng

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Furthermore, Song and colleagues showed that miR199a modulates the survival and cell proliferation by targeting Frizzled type 7 receptor (FZD7), the most important Wnt receptor involved in cancer development and progression . Recently, Shen et al (2015) showed that the expression of miR-199a and miR-125b is greatly modulated by DNA hypermethylation that plays a key role in hepatocarcinogenesis.…”

Section: Mir-199amentioning

confidence: 99%

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

Bronte

Fanale

et al. 2016

Critical Reviews in Oncology/Hematology

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“…Participants come from a previous HCC tissue study [28-30] conducted at Columbia University Medical Center (CUMC) and approved by the Institutional Review Board of CUMC. A waiver of consent was given in the study because the majority of patients died before the research was carried out.…”

Section: Methodsmentioning

confidence: 99%

“…These data have been deposited in NCBI's Gene Expression Omnibus database (accession number GSE54751). [29,30] …”

Section: Methodsmentioning

confidence: 99%

Evaluating normalization approaches for the better identification of aberrant microRNAs associated with hepatocellular carcinoma

Shen

Wang

Gurvich

et al. 2016

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Aim Dysregulated microRNAs (miRNAs) have been identified in hepatocellular carcinoma (HCC), but only a small proportion have been confirmed. An appropriate normalizer is crucial to determining the accuracy and reliability of data from miRNA studies. Methods Different normalization strategies were used to validate genome-wide miRNA profiles in HCC tumor and non-tumor tissues, and to determine the consistency and discrepancy of data on dysregulated miRNAs. Results Two sets of stable miRNAs (miR-30c/miR-30b and miR-30c/miR-126) were identified in HCC tissues by geNorm and NormFinder tools, respectively. The mean of global miRNAs also showed good stability for ranking the top 1-2 miRNAs, but the stabilities of the manufacturer-recommended ncRNAs controls were poor. Four panels of miRNAs were significantly associated with HCC by separately using various normalizers, and 14 miRNAs were consistently identified by three normalization strategies. Although fewer miRNAs (17-26) were dysregulated in HCC using the global mean or the 2 stable miRNAs as normalizers, perfect clustering of tissues was also obtained with only 1 to 2 misclassifications, suggesting the efficiency of the miRNA panels. Using global mean as the normalizer, the authors identified 7 miRNAs, including 2 novel (miR-324-5p and miR-550) significantly upregulated in HCC that were omitted when using 3 endogenous controls as the normalizer. Conclusion An optimal normalization strategy to identify biologically important miRNAs in HCC tissue studies of miRNA may be the combination of global mean and 2 stable miRNAs. Selection of appropriate normalization strategies to adjust miRNAs levels is particularly important for epidemiological studies dealing with large data sets and covering multiple experimental batches.

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Genome-Wide Expression of MicroRNAs Is Regulated by DNA Methylation in Hepatocarcinogenesis

Cited by 20 publications

References 48 publications

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

Aberrant DNA methylation of miRNAs in Fuchs endothelial corneal dystrophy

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

Evaluating normalization approaches for the better identification of aberrant microRNAs associated with hepatocellular carcinoma

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