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Study Uncovers Coordinated Transcription for Protein-Coding and RNAs

NEW YORK (GenomeWeb News) – A new study suggests a significant proportion of long, non-coding RNAs, or lncRNAs, are transcribed in cahoots with neighboring messenger RNAs in mammalian stem cells.

Researchers from the Whitehead Institute for Biomedical Research, the Massachusetts Institute of Technology, and elsewhere used several sequencing techniques to profile lncRNA patterns in embryonic stem cells from mice and humans. Findings from these experiments, published online yesterday in the Proceedings of the National Academy of Sciences, suggested that some 60 percent or more of lncRNAs arise through divergent transcription at active gene promoters.

"At any one of the 20,000 protein-coding genes that are active in human stem cells, a lncRNA gene located upstream is also transcribed," senior author Richard Young, a biologist based at the Whitehead Institute and MIT, said in a statement.

"So much effort has gone into studying protein-coding genes, and yet we have missed this concept that all protein-coding genes come in mRNA/lncRNA pairs," he continued. "If you activate the mRNA gene, you're going to activate the lncRNA gene."

This lncRNA transcription typically ran in the opposite direction of the transcription of the corresponding mRNAs, the researchers found, with levels of paired lncRNAs and mRNAs rising and falling together in human embryonic stem cells differentiating into more mature cell types.

Past research has implicated lncRNAs in a range of regulatory processes in mammalian cells — from gene silencing to development — authors of the new study said. For the most part, though, studies so far have focused on lncRNAs at the already-spliced stage, leaving questions about just how these molecules are produced in the genome.

"Many [lncRNA] species have been identified in mammalian cells," they wrote, "but the genomic origin and regulation of these molecules in individual cell types is poorly understood."

To look at the overall collection of lncRNAs produced in stem cells, the researchers brought together new and existing data on RNAs in human embryonic stem cells and other human tissues.

For their own analyses of the human embryonic stem cells, for instance, the investigators turned to sequencing strategies such as directional RNA sequencing, which looks at RNAs produced from each DNA strand, as well as global run-on sequencing, a method for assessing newly formed RNA transcripts.

After tossing out short RNAs, RNAs supported by relatively few reads, repeats, or transcripts suspected of coding for proteins, the team narrowed in on a list of more than 3,500 predicted lncRNAs in human embryonic stem cells. Almost three-quarters of those had not been reported in the past, the researchers said, and 89 percent came from parts of the genome containing gene promoters, enhancers, or gene bodies.

The team's subsequent analyses indicated that proposed lncRNAs turned up with unexpected frequency around active protein coding genes, often being produced in a divergent and/or antisense fashion relative to the nearby coding mRNA.

"Inspection of the data at individual genes shows that this divergent transcription is associated with lncRNA/mRNA gene pairs," the study's authors said, "consistent with the model that these lncRNAs are produced as a result of divergent transcription from promoters of active protein-coding genes."

Such patterns did not seem to stem from coincidental transcription at lncRNA sequences and nearby protein-coding genes, they added. On the contrary, results of their analyses hinted at coordinated transcription of lncRNA-mRNA pairs in the human embryonic stem cell genome.

When these stem cells were nudged into differentiating, for instance, lncRNA production tended to jump or dip in concert with changes to corresponding mRNAs.

Despite the widespread transcription of lncRNAs, though, the group's findings indicate that only a fraction of the molecules stick around to contribute to the cell's steady-state collection of lncRNAs.

"The GRO-seq data for [human embryonic stem cells] shows that divergent transcription occurs at the vast majority of protein-coding genes where transcription initiation takes place," Young and co-authors wrote, "but the RNA-seq data indicate that only a small fraction of the divergent transcription events produce substantial levels of steady-state lncRNAs."

In their follow-up experiments, the researchers saw signs of similar lncRNA-mRNA ties in embryonic stem cells from mice, too, consistent with some co-regulation of lncRNAs and mRNAs molecules in both of the mammalian stem cells tested.

"Future studies of lncRNA/mRNA gene pairs and the lncRNAs described here should provide new insights into the contributions of lncRNAs to the control of cell state and the process of differentiation," the study authors concluded.