Genomic Wormholes May Be Shortcuts to Breast Cancer

September 22, 2014
Genomic Wormholes May Be Shortcuts to Breast Cancer
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How may far-separated objects quickly come into proximity and directly influence each other? In this universe, wormholes are just the thing, at least on the very largest scales. When space curves upon itself, once-distant locations may intersect, say cosmologists and sci-fi gurus, making the universe a more interesting place—one needn’t take light years to traverse unimaginably vast stretches of emptiness.

The universe known as the genome, too, has stretches of seeming nothingness. Called “gene deserts,” these are regions of noncoding DNA or so-called junk DNA. Though far, far away from protein-coding regions, gene deserts are home to lone, single-letter DNA variations that somehow manage to affect the activity of key genes and thereby influence health and disease.

As in the universe at large, there are curves of a sort—or more accurately loops—that occur in the genomic universe. They can bring seemingly isolated variations close to DNA sequences that are directly involved in protein synthesis and cellular function.

That’s the idea. If scientists could identify specific looping interactions, they could solve long-standing mysteries. For example, they could clarify how is it that most of the 70 or so DNA variants associated with breast cancer occur in noncoding regions of DNA. Several of these variants map to gene deserts, regions of several hundred kb lacking protein-coding genes.

Unfortunately, scientists have had difficulty exploring and taking the measure of genomic loops. They have tried in vain to characterize looping interactions, to say nothing of trying to modify them for therapeutic purposes.

Enter Capture Hi-C, a technology that “fishes” for physical interactions between regulatory elements and their target genes. The technology, developed by researchers at the Institute of Cancer, London, has been used to identify where gene desert DNA was most likely to bind with DNA elsewhere, including with known breast cancer genes.

The details appeared September 22 in the journal Genome Research, in an article entitled, “Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C.”

“We used CHi-C to investigate long range interactions at three breast cancer gene deserts mapping to 2q35, 8q24.21, and 9q31.2,” wrote the authors. “We identified interaction peaks between putative regulatory elements (‘bait fragments’) within the captured regions and ‘targets’ that included both protein coding genes and long non-coding (lnc)RNAs, over distances of 6.6 kb to 2.6 Mb.”

After reviewing previous approaches to interaction fishing, which included various chromosome conformation capture (3C) techniques and their refinements (up to 4C and even 5C), the authors described the advantages of their “Hi-C” approach. Instead of searching for matches between bait fragments and targets in “one by one,” “one by all,” or even “many by many” fashion, Hi-C searches “all by all”; that is, it provides genome-wide coverage of all possible interactions.

According to Capture Hi-C’s developers, who were led by Olivia Fletcher, Ph.D., a genetic epidemiologist at the Institute of Cancer Research, the technology is an enhanced Hi-C protocol. It overcomes resolution limitations that bedeviled earlier Hi-C approaches by incorporating a sequence capture step. This innovation, asserted the authors of the Genome Research article, allows “high-resolution analysis of all interactions for which one end of the di-tag (the bait end) maps to a pre-specified genomic region (the capture region) and the location of the other end (the target end) is unrestricted (‘many-by-all’).”

“Target protein-coding genes were IGFBP5, KLF4, NSMCE2, and MYC, and target lncRNAs included DIRC3, PVT1 and CCDC26,” the authors reported. “For one gene desert, we were able to define two SNPs (rs12613955 and rs4442975) that were highly correlated with the published risk variant and that mapped within the bait end of an interaction peak.”

“Our research suggests that some of [the single-letter variations in noncoding DNA] may be raising the risk of breast cancer by physically interacting with genes in distant parts of the genome, in order to turn their activity up or down,” said Dr. Fletcher. “Our study provides important clues about the causes of breast cancer, as well as shining a light on the roles played by gene deserts—fascinating, gene-less regions of DNA, the mystery of which we are only just beginning to understand.”

Kat Arney, Ph.D., science communications manager at Cancer Research UK, said: “It’s becoming increasingly clear that the DNA in-between our genes is full of important control switches that turn genes on and off, yet relatively little is known about this ‘dark matter’ within our genome. Studies like this are vital if we’re to understand how DNA changes—whether within or outside genes—affect cancer risk and tumor growth, and to develop more effective treatments based on that knowledge.”