Micro RNAs and the Link between DNA Demethylation and Cancer-Associated Gene Expression

DNA exists in a highly condensed state and dna methylation is one of the most common mechanism in gene silencing. Methylation at the cpg islands plays a major role in gene expression and the loss of the methylation leads to gene expression. the genes that have the transcription limited to the germ cells have the genes silenced predominantly by this method. These genes are often referred to as cancer germline (CG) genes, commonly found in the X chromosome and are strictly methylated. 

CT- GABRA3 transcript (Cancer Testis Gamma-Aminobutyric Acid Type A Receptor Subunit Alpha3) is normally found in the testis for a specific function but can be activated in tumors due to hypomethylation, is a variant of GABRA3 (present in brain and testis). Both the variants carried pair of mi RNAs miR105 and miR767, miR105 inhibits the expression of ZO-1  a tight junction protein in endothelial cells facilitating the migration of  cancer cells and miR767 targets and inhibits TET1 and TET3 from the TET family of genes that are responsible for localised DNA demethylation of 5-methylcytosines to 5-hydroxymethylcytosines. The knockdown of miR767 resulted in reduced TET1 and TET3 mRNA levels and inhibited the TET1 and TET3 protein levels. 

(A) schematic representation of the human GABRA3 locus. The exon/intron structure of the referenced GABRA3 transcript and of the newly characterized transcript variant (CT-GABRA3) is shown below.
(B) Expression analysis of GABRA3, miR-105 and miR-767 in normal human tissues, melanocytes, and in melanoma cell lines 

When compared to the other miRNAs miR767 is only present in certain tissues (brain and testis) and in a wide variety of cancer. The miR767 has a link between DNA methylation and TET genes, TET proteins act as "erasers" that remove the methyl groups in 5mc demthylating the DNA. This results in the transcription of the miR767 which in turn inhibits the TET enzymes leading to further epigenetic remodelling by local and specific hypermethylation. This could mean that miR767 played a major role in developing the germ line cells. TET1 was found to be downrwgulsted by neuronal activity showing that it could have a role in memory formation. It was found that the cancer germline gene produces micro RNAs with oncogenic potential and how the miRNAs target TET and contribute to DNA hypomethylation.

Reference:

Loriot, A., Van Tongelen, A., Blanco, J., Klaessens, S., Cannuyer, J., van Baren, N., Decottignies, A., & De Smet, C. (2014). A novel cancer-germline transcript carrying pro-metastatic miR-105 and TET-targeting miR-767 induced by DNA hypomethylation in tumors. Epigenetics, 9(8), 1163–1171. https://doi.org/10.4161/epi.29628

Image Source:

• https://contractlaboratory.com/epigenetics-and-gene-expression/
• https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4de2/4164501/17555409fe1c/epi-9-1163-g1.jpg