Research group studies the regulatory role of a non-coding gene in a region containing a tumor-suppressor gene, but on the opposite strand of the DNA (photo: NASA)

Brazilian discovery paves the way to more specific gene modulation
2013-12-11

Research group studies the regulatory role of a non-coding gene in a region containing a tumor-suppressor gene, but on the opposite strand of the DNA.

Brazilian discovery paves the way to more specific gene modulation

Research group studies the regulatory role of a non-coding gene in a region containing a tumor-suppressor gene, but on the opposite strand of the DNA.

2013-12-11

Research group studies the regulatory role of a non-coding gene in a region containing a tumor-suppressor gene, but on the opposite strand of the DNA (photo: NASA)

 

By Karina Toledo

Agência FAPESP – In the not very distant past, the portion of the genome that does not contain information for the production of proteins – roughly 98% of the genetic code – was considered by science to be “junk DNA.” However, new studies have shown that it is precisely through this DNA that RNAs perform other important epigenetic functions, those that modulate the functions of neighboring genes.

All research conducted to date has been focused on noncoding protein genes. However, a group of Universidade de São Paulo (USP) scientists uncovered, for the first time, a noncoding gene functioning on the opposite strand of DNA and discovered that it also acts as a modulator but in a much more specific manner. The results were published in the August edition of PLoS Genetics.

“The DNA molecule is formed by a double strand of complementary nucleotides, which are reverse copies. All proteins are coded by genes located on only one of these strands,” explained Sergio Verjovski-Almeida, researcher at USP’s Chemistry Institute and coordinator of the FAPESP-funded study.

The researchers began by identifying and investigating a gene on the complementary strand (located in the same region of the genome but on the opposite DNA strand) of the gene encoding RASSF1, a protein that inhibits tumor growth.

“This protein is produced in four different versions: RASSF1A, RASSF1B, RASSF1C and RASSF1D. The RASSF1A isoform has a tumor-suppressing function that has been well documented in the scientific literature. The RNA produced from the opposite strand, which we call ANRASSF1, is the counter sequence and does not encode a protein,” explained Verjovski-Almeida.

The group’s first challenge was finding the tools to change the expression of ANRASSF1 without altering its gene-coding function. “Normally, to characterize a gene’s function, one either induces a mutation or removes that piece of DNA, a method known as deletion, to see what happens. However, we could not do that without affecting the RASSF1 gene,” said Verjovski-Almeida.

The group therefore began using a plasmid – circular DNA – containing genetic material capable of interfering with ANRASSF1 expression. By testing the method in breast and prostate cancer cell lines, the scientists found that, when this noncoding RNA was overexpressed, RASSF1A activity dropped to 10% to 20% of normal, without affecting the production of the other isoforms of the protein.

The researchers also found that the greater the quantity of ANRASSF1 present, the lower the production of RASSF1A and the greater the growth of tumor cells. According to Verjovski-Almeida, this discovery paves the way to new anti-cancer treatments that inhibit ANRASSF1 expression.

Tip of the iceberg

“Until recently, the role of intergenic noncoding genes, i.e., those located in the DNA between coding genes, was unknown. We now know that intergenic sequences have the capacity to silence several neighboring genes. The antisense noncoding sequence that we studied is different because its regulatory function is local and specific to only one of the isoforms of the RASSF1 gene,” explained Verjovski-Almeida.

For the authors of the article published in PLoS Genetics, the discovery represents only the tip of the iceberg because there are thousands of other genes that express similar antisense RNAs, which possibly have an epigenetic role in humans.

“In a previous study, we showed that 70% of protein-coding genes have at least one section transcribed on the opposite strand. Today, there are studies showing that 90% have noncoding RNAs transcribed on the opposite strand. This class of RNA that, until recently, was considered useless should be investigated gene by gene for implementation as a tool for the highly specific modulation of important genes,” related Verjovski-Almeida.

The article The Intronic Long Noncoding RNA ANRASSF1 Recruits PRC2 to the RASSF1A Promoter, Reducing the Expression of RASSF1A and Increasing Cell Proliferation (doi: 10.1371/journal.pgen.1003705) can be read at www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1003705.

 

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