A team of scientists from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) and their collaborators from the Harvard Stem Cell Institute have found that a novel noncoding ribonucleic acid (RNA) offers the potential for "switching on" of tumour suppressors that have been shut off.
The research group, led by Professor Daniel Tenen, Director of CSI Singapore, demonstrated for first time that RNA interacts with an enzyme essential for DNA methylation, known as DNA methyl transferase 1 (DNMT1), offering strategies for the treatment of diseases such as cancer.
In this study, the researchers focused on a new class of RNAs, which is critical in regulating DNA methylation. This is a process in which certain building blocks of DNA, the genetic code, are chemically modified without resulting in a change in the code itself. DNA methylation is associated with silencing of gene expression and found in many diseases. For example, in cancer, genes called tumour suppressors, which inhibit tumour formation, are often silenced or shut off in the cancer cells, and this is associated with DNA methylation.
This novel study was first published online in the research journal Nature on 9 October 2013.
How the novel noncoding RNA inhibits DNA methylation
The study focused on this novel noncoding RNA in a specific tumour suppressor, known as CEBPA. The silencing of CEPBA is associated with Acute Myeloid Leukemia, lung cancer and other types of cancer. The scientists demonstrated that the noncoding RNA binds to the enzyme DNMT1 and prevents DNA methylation of the CEBPA gene. This principle, which is likely to extend to thousands of other genes, can potentially be used to "switch on" tumour suppressors that have been shut off.
Prof Tenen said, "We started out by studying the noncoding RNA to satisfy our scientific curiosity. In the process, we discovered the novel finding that RNA inhibits methylation and experimentally, we can introduce RNAs to 'switch on' tumour suppressors which have been shut off. Our results suggest strategies for gene-selective demethylation of therapeutic targets in human diseases such as cancer."
In the next phase of their research, the scientists will look into developing tools for targeted activation of other tumour suppressors, besides CEBPA, and investigate the role of RNA in regulating other epigenetic marks.
- Annalisa Di Ruscio, Alexander K. Ebralidze, Touati Benoukraf, Giovanni Amabile, Loyal A. Goff, Jolyon Terragni, Maria Eugenia Figueroa, Lorena Lobo De Figueiredo Pontes, Meritxell Alberich-Jorda, Pu Zhang, Mengchu Wu, Francesco D’Alς, Ari Melnick, Giuseppe Leone, Konstantin K. Ebralidze, Sriharsa Pradhan, John L. Rinn, Daniel G. Tenen. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature, 2013; DOI: 10.1038/nature12598
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