A research Broad Institute of Harvard and MIT and Beth Israel Deaconess Medical Center using mouse cells has uncovered a set of genes that do not encode proteins , but instead function as long RNA molecules. Prior to the finding, only 10 examples of the large intervention non-coding RNAs, called lincRNAs, had been found, and they were dismissed as genomic oddities rather than critical elements.
In reality, thousands of these genes have been conserved during mammalian evolution, and the lincRNAs themselves are thousands of bases long, the scientists note. The team has determined that the 1,586 loci they found so far play critical roles in immune signaling, stem cell biology, and cancer.
“The challenge in finding these lincRNAs is that they have been hiding in plain sight,” says John Rinn, Ph.D., a Harvard Medical School assistant professor at Beth Israel Deaconess Medical Center. “The human and mouse genomes are already known to produce many large RNA molecules, but the vast majority show no evolutionary conservation across species, suggesting that they may simply be “genomic noise” without any biological function.”
To uncover this large collection of new genes, the research team looked for telltale chromatin modifications. They searched for genomic regions that have the same chromatin patterns as protein-coding genes but do not encode proteins. The group surveyed the genomes of four different types of mouse cells including embryonic stem cells.
“The epigenomic marks revealed where these genes were hiding,” says Mitch Guttman, an MIT graduate student working at the Broad Institute. “Analysis of their sequence then revealed that the genes are highly conserved in mammalian genomes, which strongly suggested that these genes play critical biological functions.”
By correlating the expression patterns of lincRNAs in various cell types with the expression patterns of known critical protein-coding genes in those same cells, the scientists observed that lincRNAs probably play important regulatory roles in a variety of cellular processes including cell proliferation, immune surveillance, maintenance of embryonic stem cell pluripotency, neuronal and muscle development, and gametogenesis.
The scientists say it is likely that there are many more lincRNA genes hiding in plain sight in the genome as well as other RNA-encoding genes that are as important to genome function as their better-recognized protein-coding counterparts.
“We’ve known that the human genome still has many tricks up its sleeve,” says Eric Lander, Ph.D., founding director of the Broad Institute. “But it is astounding to realize that there is a huge class of RNA-based genes that we have almost entirely missed until now.”
The findings are presented in the February 1 advance online issue of the journal Nature.