MicroRNA Expression Is Regulated by DNA Methylation: a Complex Cascade Of Gene Regulation Events

MicroRNAs, or more commonly referred to as, miRNAs, are non-coding RNAs. These miRNAs are around 22 nucleotides in size that are central and negative regulators of gene expression. RNA extraction kits are used to enable the total RNA extraction from tissues and other places.They apply their abilities and functions with the help of base-pairing using 3’UTR if mRNAs. Moreover, the block expression at the post-transcriptional levels and transcriptional levels, on the basis of perfect or imperfect match in sequences among miRNAs and target genes is also there. 

miRNAs are usually the central nodes in several biological process. These include cell proliferation, apoptosis, migration, differentiation, and more. These miRNAs are known to be the “epigenetic controllers” since they impact gene expression without brining any changes in the genomic sequence. Changed and manipulated expression of miRNAs is commonly seen in several pathological conditions like cancer. In cancer, they act as tumor suppressor genes and sometimes as oncogenes. Just like the protein coding genes, miRNAs are also influenced to epigenetic changes and regulation by DNA methylation in their respective promoter regions. The DNA methylation of miRNAs has an indirect impact on the regulation of the miRNA target genes. This sometimes silences or overexpresses them, especially in the case of hypo- or hypermethylation of miRNAs. 

Furthermore, DNA methylation patterns are sometimes also impacted and subsequently altered in cancer. Most commonly aberrant methylation is not confined to few genes. The changes occur all throughout the genome region. As a result, the functionalities of DNA methylation are highly dependent on context and therefore have a completely opposite impact on gene expression, especially if it happens in the promoter of a coding gene or a miRNA. If DNA methylation is present at the gene promoter, this can result in the downregulation of the gene. That being said, the DNA methylation of miRNAs also is a big factor that leads to overexpression in the target genes. Also, miRNAs have the ability to influence the expression of several targets. As a result, the gene targets can be regulated with the help of a plethora of different miRNAs, simultaneously. This creates a great network of miRNAs-targets that greatly enhances the complexity of gene regulation. 

In order to give clear working on how DNA methylation and miRNAs work together to change the gene expression, scientists have thoroughly evaluated the effects of miRNA DNA methylation on many genes that take part in Neuroblastoma; a tumor found in infancy. Researchers identified four miRNAs that were miR34b, miR34c, miR149, and miR124-2. All of these were subjected to DNA methylation in their respective regulatory regions. As a surprise, it was found out that these miRNAs share many targets (CDK4, E2F1, E2F3, CCND1, CCNE2, BCL2, MYCN, and CDK6). All these are the central actors in cell cycle and apoptosis pathways taking part in the pathogenesis of Neuroblastoma. Scientists further worked showed that despite of the differences between cell lines in the gene expression level, the miRNAs-gene network is very slightly influenced or disrupted in these pathways. An epigenetic drug called 5’Azacytidine is used for treatment, which induces global demethylation of the genome. This also showed that there is an inverse correlation between methylation statuses of the above mentioned miRNAs along with the expression of their gene targets. 

All in all, the data shows a very complex, multi-level interaction of all the epigenetically changed and influenced miRNAs that weren’t able to completely regulate the cell cycle. This lead to decreased effectiveness in the apoptotic process. This reveals that DNA methylation regulates gene expression on a rich profusion of levels, and regulates cell homeostasis along with cancer progression. Scientists consider this data to be able to solve many more answers in the longer run like how to get additional miRNAs under control of DNA methylation, or the influencing cell cycle and apoptosis. On the other hand, the miRNAs examined in this study can also be used to target other genes and pathways. Moreover, other literature and studies have demonstrated that many genes are directly silenced by methylation, and not by miRNAs. (Banelli 2016)

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