Scientists at Sydney’s Centenary Institute report that the 97% of human DNA long referred to as junk can actually play a significant role in controlling cell development.
Based in the institute’s gene and stem cell therapy program, the researchers say they have unraveled a previously unknown mechanism for regulating the activity of genes, thus increasing our understanding of the way cells develop and pointing to new possibilities for therapy.
Using gene-sequencing methodologies and advanced computer analysis, John Rasko, Ph.D., and a team including Centenary’s head of bioinformatics, William Ritchie, Ph.D., showed how particular white blood cells use non-coding DNA to regulate the activity of a group of genes that determines their shape and function. The work is published today in Cell.
“This discovery, involving what was previously referred to as ‘junk,’ opens up a new level of gene expression control that could also play a role in the development of many other tissue types,” said Dr. Rasko, noting that the researchers arrived at their conclusions by studying noncoding introns. “Our observations were quite surprising, and they open entirely new avenues for potential treatments in diverse diseases including cancers and leukemias.”
As part of the normal process of generating proteins from DNA, the code for constructing a particular protein is printed off as messenger RNA (mRNA). It is this strip of mRNA which carries the instructions for making the protein from the gene in the nucleus to the protein factories or ribosomes in the body of the cell.
But these mRNA strips need to be processed before they can be used as protein blueprints. Typically, any non-coding introns must be cut out to produce the final sequence for a functional protein. Many of the introns also include a stop codon which, if left in, stops protein construction altogether. Retention of the intron can also stimulate a cellular mechanism which breaks up the mRNA containing it.
Dr. Ritchie was able to develop a computer program to sort out mRNA strips retaining introns from those which did not. Using this technique, the lead molecular biologist of the team, Justin Wong, Ph.D., found that mRNA strips from many dozens of genes involved in white blood cell function were prone to intron retention and consequent breakdown. This was related to the levels of the enzymes needed to chop out the intron. Unless the intron is excised, functional protein products are never produced from these genes. The team’s Jeff Holst, Ph.D., went a step farther to show how this mechanism works in living bone marrow.
So the researchers propose that intron retention is an efficient means of controlling the activity of many genes. “In fact, it takes less energy to break up strips of mRNA than to control gene activity in other ways,” explained Dr. Rasko. “This may well be a previously overlooked general mechanism for gene regulation with implications for disease causation and possible therapies in the future.”