[biomed] new class of nonprotein coding genes in mammals with key functions

[Eugen Leitl]

http://www.geneticstimes.com/Research/Scientists_uncover_new_class_of_nonprotein_coding_genes_in_mammals_with_key_functions.asp

Scientists uncover new class of nonprotein coding genes in mammals with key
functions (2/3/2009)

Tags: rna, genomics, epigenomics, lincrnas

A research team at the Broad Institute of Harvard and MIT and Beth Israel
Deaconess Medical Center has uncovered a vast new class of previously
unrecognized mammalian genes that do not encode proteins, but instead
function as long RNA molecules. Their findings, presented in the February 1st
advance online issue of the journal Nature, demonstrate that this novel class
of "large intervening non-coding RNAs" or "lincRNAs" plays critical roles in
both health and disease, including cancer, immune signaling and stem cell
biology.

"We've known that the human genome still has many tricks up its sleeve," said
Eric Lander, founding director of the Broad Institute and co-senior author of
the Nature paper. "But, it is astounding to realize that there is a huge
class of RNA-based genes that we have almost entirely missed until now."

Standard "textbook" genes encode RNAs that are translated into proteins, and
mammalian genomes harbor about 20,000 such protein-coding genes. Some genes,
however, encode functional RNAs that are never translated into proteins.
These include a handful of classical examples known for decades and some
recently discovered classes of tiny RNAs, such as microRNAs.

By contrast, the newly discovered lincRNAs are thousands of bases long.
Because only about ten examples of functional lincRNAs were known previously,
they seemed more like genomic oddities than critical components. The new
Nature study shows that there are actually thousands of such genes and that
they have been conserved across mammalian evolution.

"The challenge in finding these lincRNAs is that they have been hiding in
plain sight," said John Rinn, a Harvard Medical School assistant professor at
Beth Israel Deaconess Medical Center and an associate member of the Broad
Institute of Harvard and MIT. "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 Broad scientific team
looked not at the RNA molecules themselves but at telltale signs in the DNA
called chromatin modifications or epigenomic marks. They searched for genomic
regions that have the same chromatin patterns as protein-coding genes, but do
not encode proteins. By surveying the genomes of four different types of
mouse cells (including embryonic stem cells and cells from various tissue
types), they found an astounding 1,586 such loci that had not been previously
described. The researchers also found that the vast majority of these genomic
regions are transcribed into lincRNAs, and that these are conserved across
mammals.

"The epigenomic marks revealed where these genes were hiding," said Mitch
Guttman, a 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 likely play critical roles in
helping to regulate a variety of different cellular processes, including cell
proliferation, immune surveillance, maintenance of embryonic stem cell
pluripotency, neuronal and muscle development, and gametogenesis. Further
experimental evidence from several of the identified lincRNAs verified these
observations.

Because of the stringent experimental conditions imposed by the researchers
in identifying the 1,600 lincRNAs in the Nature study, 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.

Note: This story has been adapted from a news release issued by the Broad
Institute of MIT and Harvard