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. 2014 Jun 30;2(2):e18.
doi: 10.15190/d.2014.10.

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

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Free PMC article

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

Ziga Strmsek et al. Discoveries (Craiova). .
Free PMC article

Abstract

There is an increasing research interest regarding deregulation of microRNA (miRNA) expression by DNA methylation in cancer. The aim of this study was to integrate data from publications and identify miRNA genes shown to be silenced in the highest number of cancer types and thus facilitate biomarker and therapeutic development. We integrated relevant data from 104 published scientific articles. The following databases and bioinformatics tools were used for the analysis: miRBase, miRNA Genomic Viewer, MultAlin, miRNA SNiPer, TargetScan, Ensembl, MethPrimer, TarBase, miRecords, and ChIPBase. Among 2578 currently known human miRNAs and 158 known to be regulated by DNA methylation, miR-34 gene family (miR-34a, -34b, and -34c) was shown to be silenced by DNA methylation in the highest number of cancer types. Consequently, we developed the miR-34 gene family regulatory atlas, consisting of its upstream regulators and downstream targets including transcription factor binding sites (TFBSs), CpG islands, genetic variability and overlapping QTL. MicroRNA-34 gene family has a potential as a cancer biomarker and target for epigenetic drugs. This potential has already been recognized as MRX34 is well into phase I studies. The developed miR-34 gene family regulatory atlas presented in this study provides a starting point for further analyses and could thus facilitate development of therapeutics.

Keywords: DNA methylation; Kunej; Slovenia; Tanja; University of Ljubljana; cancer; miR-34; miRNA; microRNA.

Conflict of interest statement

Conflict of interests: The authors do not declare any conflict of interest.

Figures

Figure 1
Figure 1. MicroRNA genes shown to be regulated by DNA methylation in more than nine cancer types
The number in bracket represents the number of reports describing the association between miRNA gene that is silenced by DNA methylation and cancer type. The darker the colour, the stronger association between miRNA gene and cancer type. ALL (acute lymphoblastic leukemia), AML (acute myeloid leukemia), CML (chronic myelogenous leukemia), CLL (chronic lymphocytic leukemia), NHL (non-Hodgkin lymphoma). Bone marrow cancer consists of myeloproliferative neoplasms, myeloma and lymphoma.
Figure 2
Figure 2. A miR-34 gene family regulatory atlas
An atlas integrates relevant genomic data regarding DNA methylation, histone modifications, CpG islands, upstream regulators, downstream targets and genetic variability.
Figure 3
Figure 3. Genomic location of miR-34-a, -b, and –c genes and overlapping QTL
Analysis was performed using miRNA genomic viewer and revealed that all three members of the miR-34 family genes overlapped with QTL for prostatic neoplasms
Figure 4
Figure 4. CpG island analysis of miR-34 family and SNPs that could affect gain/loss of DNA methylation sites
One CpG island is located upstream of the miR-34a gene. Three CpG islands are located upstream of the miR-34b/c gene region and miR-34b is embedded in the CpG island. Promoter for miR-34b/c is birectional and it also regulates BTG4. Six SNPs overlap CpG dinucleotides within promoter regions: one SNP is located upstream of miR-34a gene and five upstream of the miR-34b/c gene.
Figure 5
Figure 5. Alignment of the miR-34 family pre-miRNA sequences and experimentally validated targets of the miR-34 gene family
a) Alignment of pre-miRNA sequences of miR-34 gene family. Red nucleotides are present in all three members of miR-34 gene family, blue nucleotides are present in two members of miR-34 gene family. Seed regions are represented in squares. b) Experimentally validated targets of miR-34 family genes.
Figure 6
Figure 6. Proposed decision tree for identification of miRNA genes silenced by DNA methylation in cancer

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