Tiny proteins known as micropeptides can play key roles in developmental biology. These molecules are encoded by equally little bits of DNA known as short or small open reading frames that often escape detection amidst an extraordinary number of meaningless junk sequences. Now two recent papers find that potentially crucial micropeptide-encoding genes might lurk in overlooked places in genomes, possibly pointing to new drug targets.
The Human Genome Project revealed we each possess roughly 20,000 protein-coding genes, but since then scientists have also discovered more than 10,000 so-called long non-coding RNAs (lncRNAs) that are transcribed from the human genome, molecules more than 200 nucleotides long. However, a small percentage of transcripts that originally appeared to be lncRNAs may actually encode micropeptides.
Molecular biologist Eric Olson at the University of Texas Southwestern Medical Center and his colleagues found a putative lncRNA encoded a 46-amino-acid micropeptide they call myoregulin. Myoregulin is structurally similar to phospholamban, which is found in heart tissue, and sarcolipin, which is found only in slow twitch skeletal muscle. Phospholamban and sarcolipin inhibit SERCA, a membrane protein that controls muscle relaxation and contraction by regulating the amount of calcium ions stored in muscle cells. The researchers discovered myoregulin plays the same role in all skeletal muscle.
“I find it surprising and refreshing that a regulator like myoregulin has gone undiscovered all this time,” Olson says. “This really shows how much more is left to discover, even about processes we thought we knew all about.” He and his colleagues detailed their findings in the February 12 issue of the journal Cell.
Myoregulin could be used as a target for enhancing skeletal muscle performance. “These findings also point to the potential existence of a world of micropeptides waiting to be discovered,” Olson says, adding that they have already found other members of the myoregulin family mis-annotated as lncRNAs that code for micropeptides as well.
In separate work, biogerontologists Changhan David Lee and Pinchas Cohen at the University of Southern California and their colleagues discovered that micropeptides can also lurk in mitochondria. The 16-amino-acid micropeptide they name MOTS-c is a hormone that primarily targets skeletal muscle, where it helps control insulin sensitivity.
“This represents a paradigm shift in biology whereby the mitochondria communicate to regulate metabolism at the cellular and organismal level using its own inherent mediators,” Lee says. He, Cohen and their colleagues detailed their findings in the March 3 issue of the journal Cell Metabolism.
In experiments in mice, the researchers found injections of MOTS-c could suppress the obesity and insulin resistance the rodents would normally get from a high-fat diet, and also reversed age-dependent insulin-resistance, a condition that precedes diabetes. “MOTS-c may provide a previously unknown mitochondrial-centric drug target for metabolically relevant diseases and aging,” Lee says. He thinks there are other short open reading frames in the mitochondrial DNA that encode for biologically significant small peptides.
These findings support the idea that “there is a hidden world of active small peptides hidden in genomes,” says molecular biologist John Mattick, executive director at the Garvan Institute of Medical Research in Australia, who did not take part in these studies. He estimates that roughly 2 percent of sequences that seem like lncRNAs may harbor active peptides that have yet to be discovered.