Even well-known diseases hide some mysteries. For example, around 40% of the population have the gene variants associated with celiac disease… luckily only 1% of them suffers from intestinal inflammation after ingesting gluten — the hallmark of the disease. So what does protect individuals with these mutations from developing the gluten intolerance?
Here, the non coding DNA, comes into play; however not in the form of DNA. To exert some functions, some genomic regions (such as genes) need to first be transformed into RNA (via transcription, see here). RNA is best known as the molecule at the half way between coding DNA and proteins – but in the recent years it appears to have many other roles related to the regulation of cellular processes. RNAs derived from non-coding DNA longer than 200 nucleotides are called “long non-coding RNA” (lncRNA – scientists really love abbreviations) and one of them seems to be responsible for the protection against celiac disease.
A team of scientists first noticed some SNPs related to the celiac disease located in a non-coding DNA region transcribed into a long non-coding RNA, known as lnc13. The team, led by researchers from Columbia University, analyzed the quantity of lnc13 in the layer of cells that covers the intestine (the intestinal epithelium, the main tissue involved in celiac disease) and found that people with the disease have unusually low levels of lnc13 compared to healthy people. This oddity fostered further analyses about the relationship of lnc13 with inflammatory molecules and genes, given their importance in celiac disease. And indeed the reduction of lnc13 brought a clear increase in the activity of some known pro-inflammatory genes (Fig 2a). This suggest that lnc13 acts as a sentinel that keeps under control the inflammatory reaction. In the absence of the sentinel, any trigger like eating a piece of bread full of gluten, can provoke an inflammation in the intestinal epithelium.They also discovered that lnc13 acts inside the nucleus, where it interacts with the DNA to modulate the gene expression. However, here it does not act alone, but binding another protein (hnRNPD) (Fig 2b). Some celiac-associated SNP variants in the lnc13 region prevent such binding and consequently hinder the protective function of lnc13.
As often happens in science, one answer opens up more questions: which factors do decrease the levels of lnc13? Is lnc13 responsible for the acquired gluten intolerance in adults? More answers might be hidden in the non-coding portion of the DNA.