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Effects Of microRNAs Extend Beyond Single Genes

September 23, 2010

When Dr. David Corry and his colleagues at Baylor College of Medicine (www.bcm.edu) and the University of Houston (www.uh.edu)  inhibited the activity of some microRNAs that prevent production of a cytokine associated with asthmatic lung disease in mice, they thought the animals’ disease would get worse.

Instead, the disease diminished ““ a result diametrically opposed to what they expected and an example of the complexity of working with these tiny slivers of genetic material that serve as on and off switches for genes, said Corry, professor of medicine-pulmonary at BCM. A report on his research appears in the current issue of the Journal of Biological Chemistry (http://www.jbc.org/).

MicroRNAs are short sequences (about 22 or 23 nucleotides long) of RNA that act as switches.

“If they recognize a particular gene, they will prevent the protein (associated with it) from being made,” said Corry (http://www.bcm.edu/medicine/pulmonary/index.cfm?pmid=4828). “The problem with microRNAs is that you cannot think of them in a linear fashion. You have to think of them as acting massively parallel. It’s like going from an Apple computer to one of those huge supercomputers. MicroRNAs don’t affect just one gene. They affect hundreds, even a thousand different genes simultaneously. Their sphere of influence is immense.”

A gene provides a genetic code that is eventually translated into a protein that carries out a function within a cell. MicroRNAs, however, in turning off production of a protein can set into motion a cascade of events that can turn biology upside down.

“MicroRNAs can turn off (or silence) genes, but that’s just the first order of their biology,” said Corry. “Once the process starts, then it affects the activity of other genes, which in turn affects other genes. We have no idea what these third or fourth generation effects are and there’s no mathematical algorithm to predict them.”

He and his colleagues studied the let-7 microRNAs because they make up about 70 percent of all microRNAs in lung tissue. Corry and his team focused on four let-7 microRNAs found in lung tissue. These microRNAs switched off a gene that caused production of a cellular chemical or cytokine called interleukin-13, a crucial element of asthmatic disease.

They thought that if they inhibited activity of these let-7 microRNAs, more interleukin-13 would be produced, making the disease worse.

“In fact, we got diminished disease,” Corry said. Other members of the let-7 family actually increased their expression, compensating for the loss of their family members. In fact, their activity increased so much that they suppressed the gene for interleukin-13 even more.

“It was completely unexpected,” he said. “How that compensation happens is a mystery and we will explore it in the future.”

In other words, increasing expression of a gene in one place could actually repress another gene, which could affect another gene and another.

“You get this up and down, rollercoaster effect,” said Corry.

“The future of genomics is not in the DNA but in the transcriptome (all the RNA molecules transcribed from the DNA of the genome),” he said.

Others who took part in this research include Sumanth Polikepahad, Farrah Kheradmand, John M. Knight, Lakeisha M. Batts, Preethi H. Gunaratne, Chad J. Creighton, R. Alan Harris, Azam Zariff, Chad Shaw, Cristian Coarfa and Aleksandar Milosavljevic, all of BCM, and Arash O. Naghavi, Toni Oplt, Ashley L. Benham, Jong Kim, Preethi H. Gunaratne, Benjamin Soibam and R. Alan Harris, all of UH.

Funding for this work came from the National Institutes of Health and the Clayton Foundation for Research.

Text of this report is available at http://www.jbc.org/cgi/doi/10.1074/jbc.M110.145698




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