After investigating unexplored regions of the human genome, researchers have discovered a new non-coding gene that appears to play an important role in cancer development.
The gene is in an area of the genome that does not contain instructions for making proteins. At one time, it was thought that this non-coding area was just irrelevant “junk.”
However, as technology has advanced, more and more genes are being found in this “dark matter” that are proving to be significant for health and disease.
In a paper published in the journal Cell, scientists from the University of Michigan Comprehensive Cancer Center in Ann Arbor reports that while the new gene does not code for a protein, it has a “direct impact” on cancer cells. They found that silencing it stopped tumors from growing.
The human genome contains all the instructions that are required to build and maintain cells. It carries this information in 20,000–25,000 genes in a long, winding, double-stranded molecule called DNA.
An instruction contained in DNA is not obeyed directly from there. It is first “transcribed” into a single-stranded molecule called RNA that mirrors the DNA sequence, and the total of all the transcripts held in a cell is known as the cell’s “transcriptome.”
Thus, while the genome rarely varies from cell to cell, the transcriptome varies depending on the type of cell.
By analyzing RNA, researchers should be able find out how and when the genes contained in DNA are switched on and off in different cells.
For example, it may be that analyzing the transcriptome will reveal that an unknown gene is highly expressed in cancer cells and not in healthy cells. This may indicate that the gene is important for cell growth.
The transcriptome is held in several different types of RNA. The main one, messenger RNA (mRNA), carries the script, or code, for making proteins, which are the molecules that do a lot of the work in cells. Non-coding RNAs carry scripts transcribed from DNA that do not make proteins.
For a long time, it was believed that the large part of the genome that does not contain instructions for making proteins was junk DNA. These so-called non-coding genes were also referred to as dark matter because so little was known about them.
But as sequencing technology has become more advanced, scientists have discovered that while the dark matter part of the genome may not ultimately yield proteins, it does produce non-coding RNAs that play an important role in the cell biology of health and disease.
Over the past 20 years, many new classes of non-coding RNAs have been found, including one called long non-coding RNA (lncRNA), which is a strand of RNA that has more than 200 building blocks, or nucleotides.
In the new study report, the researchers describe how they found and characterized a lncRNA that they discovered to be the same in zebrafish, mice, and humans.
This raised their curiosity because it is rare to find this type of RNA “conserved” across different species. Could this mean that it played a fundamental role in cell biology?
They named the lncRNA “Testis-associated Highly-conserved Oncogenic long non-coding RNA” (THOR).
Senior study author Arul Chinnaiyan, a professor of pathology at Michigan Medicine, says that they decided to focus on THOR because it appeared to have “been selected by evolution for having important functions.”
What the researchers discovered was that the highly conserved lncRNA is important for cancer development, and that silencing it stopped tumors from growing.
In previous work, they had already identified thousands of potential lncRNAs that might be useful to study further after mapping the landscape of the dark matter. They chose to study THOR for two reasons: firstly, because it was “evolutionarily highly conserved,” and secondly, because it was highly expressed only in one type of normal adult tissue: the testes.
Because THOR is highly conserved in zebrafish as well as humans and mice, they were able to study how it works in zebrafish models, says Prof. Chinnaiyan.
But as they investigated THOR further, they found that it was also highly expressed in some cancers, particularly melanoma and lung cancer, and that it played a direct role in cancer development.
Experiments using laboratory-grown cancer cells expressing THOR showed that silencing the gene slowed tumor growth, and that overexpressing it speeded it up. Also, normal cells lacking THOR developed normally, suggesting that it only has an effect on cancer cells.
Prof. Chinnaiyan says that they went through “a lot of lncRNAs,” and most of them did not show such a clear function as THOR.
In further experiments, the team found that THOR interacts with insulin-like growth factor-binding proteins (IGFBPs), which are thought to help keep RNAs stable. They found that silencing THOR blocked the activity of IGFBPs.
“If we perturb THOR function,” Prof. Chinnaiyan says, “we disturb the ability to stabilize RNA. This inhibits cell proliferation.” The researchers also found that overexpressing THOR caused cells to grow faster.
They suggest that THOR might serve as a target for cancer drugs because inhibiting it does not interfere with healthy cells.
“The fact that we found THOR to be a highly conserved lncRNA was exciting.”
Prof. Arul Chinnaiyan