Researchers at Stanford University School of Medicine have discovered that non-coding RNAs (ncRNAs) can influence gene expression patterns at distant locations in the cell.
"We were surprised to find that at least one of these molecules can suppress genes on a completely different chromosome," comments Howard Chang, M.D., Ph.D., assistant professor of dermatology. "This opens up the whole genome to potential regulation by ncRNAs."
The scientists were investigating how fibroblasts know where they are in the body. They previously demonstrated that, in different types of cells, the groups of genes known as HOX maintain unique patterns of expression over many generations of cell division. To understand how these patterns were determined, John Rinn, Ph.D., a postdoctoral scholar in Dr. Chang’s lab, used a tiling array to hone in on nearby regions of DNA. He was able to map the boundaries of the regions around four loci of HOX genes, known as HOXA through HOXD, to near-nucleotide resolution.
Not only did Dr. Rinn locate many previously unknown ncRNA genes among the HOX genes, he also identified areas with proteins that either activate or suppress the neighboring regions.
Additionally, the team showed that an ncRNA can affect gene expression on a chromosome other than its own. They observed that depleting the ncRNA, dubbed HOTAIR in the HOXC region on chromosome 12 of a skin cell, significantly increased the expression of HOXD genes on chromosome 2.
"Next we need to find out how these RNAs work structurally," Dr. Rinn says, "and what upstream regulatory molecules might be controlling their expression." The investigators believe that they have one clue: HOTAIR binds to and activates a group of enzymes called the Polycomb Repressive Complex 2 that modifies histones and helps them wind up the DNA.
According to the researchers., polycomb proteins are improperly regulated in some types of cancers, and it is likely that HOX gene expression patterns keep stem cells from improperly differentiating into skin, muscle, or other tissues. They believe that understanding how ncRNAs affect these processes will have implications for cancer therapies and stem cell research.
The research is published in the June 29 issue of Cell.