Illuminating the 'Dark Matter' of the Genome: Vast hidden network regulates gene expression in cancer

Researchers have uncovered a vast new gene regulatory network in mammalian cells that could explain genetic variability in cancer and other diseases.

(Credit: Image courtesy of Columbia University Medical Center)

Researchers at Columbia University Medical Center (CUMC) and two other institutions have uncovered a vast new gene regulatory network in mammalian cells that could explain genetic variability in cancer and other diseases.

The studies appear in the online edition of Cell.

"The discovery of this regulatory network fills in a missing piece in the puzzle of cell regulation and allows us to identify genes never before associated with a particular type of tumour or disease," said Andrea Califano, PhD, professor of systems biology, director of the Columbia Initiative in Systems Biology, and senior author of the CUMC research team.

For decades, scientists have thought that the primary role of messenger RNA (mRNA) is to shuttle information from the DNA to the ribosomes, the sites of protein synthesis.

However, these new studies suggest that the mRNA of one gene can control, and be controlled by, the mRNA of other genes via a large pool of microRNA molecules, with dozens to hundreds of genes working together in complex self-regulating sub-networks.

The findings have the potential to broaden investigations into how tumors develop and grow, who is at risk for cancer, and how to identify and inactivate key molecules that encourage the growth and spread of cancer.

For example, in the case of the phosphatase and tensin homolog gene (PTEN), a major tumour suppressor, deletions of its mRNA network regulators in patients appear to be as damaging as mutations of the gene itself in several types of cancer, the studies show.

The newly identified regulatory network (called the mPR network by the CUMC investigators) allows mRNAs to communicate through small bits of RNA called microRNAs.

Researchers first realized about a decade ago that microRNAs, by binding to complementary genetic sequences on mRNAs, can prevent those mRNAs from making proteins.

Turning this concept on end, the new studies reveal that mRNAs actually use microRNAs to influence the expression of other genes.

When two genes share a set of microRNA regulators, changes in expression of one gene affects the other. If, for instance, one of those genes is highly expressed, the increase in its mRNA molecules will "sponge up" more of the available microRNAs.

As a result, fewer microRNA molecules will be available to bind and repress the other gene's mRNAs, leading to a corresponding increase in expression. Although such an effect had been previously elucidated, the range and relevance of this kind of interaction had not been characterised.

"It turns out that this type of microRNA-mediated regulation is commonplace in the cell, and thousands of genes are regulating one another through hundreds of thousands of microRNA-mediated interactions," says Pavel Sumazin, PhD, research scientist in systems biology and a first author of the CUMC paper.

"This is similar in size and effect to other regulatory networks, such as transcriptional regulatory networks, where target genes are regulated by transcription factors."

In the CUMC study, Dr. Sumazin and his colleagues analyzed glioblastoma mRNA and microRNA expression data from the Cancer Genome Atlas, a public database, uncovering a regulatory layer comprising more than 248,000 microRNA-mediated interactions.

Looking specifically at the tumour suppressor gene PTEN, the researchers found that it is part of a sub-network of more than 500 genes.

Of these genes, 13 are frequently deleted in glioblastoma and seem to work together through microRNAs to stop PTEN activity -- achieving the same result as if the tumors had inactivating mutations or deletions of PTEN itself.

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