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New Study Suggests lncRNA Transcription Triggers Gene Silencing

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Researchers from the Babraham Institute this week published new data shedding light on the ways long non-coding RNAs impact gene expression, showing that the transcription of one particular lncRNA, and not the lncRNA itself, was sufficient to silence a target gene.

It is unknown if this characteristic extends to other lncRNAs, but the findings, which appeared in Science, hint at the possibility of a greater number of roles for lncRNAs in the mammalian genome than previously appreciated, according to the study's authors.

“Mammalian imprinted genes often cluster with long non-coding RNAs,” according to the Science paper. “Three lncRNAs that induce parental-specific silencing show hallmarks indicating that their transcription is more important than their product.”

One such lncRNA, Airn, is known to repress the activity of the Igf2r gene, and is believed to use different silencing mechanisms since the gene is inhibited in all embryonic, extra-embryonic, and adult tissues that express Airn, whereas two of its other targets — Slc22a3 and Slc22a2 — are only silenced in certain extra-embryonic lineages, the study's authors noted.

“In support of this, Slc22a3silencing in the placenta depends on the Airn lncRNA product recruiting EHMT2 histone methyltransferase, whereas Igf2r silencing does not,” they added.”Igf2r silencing is also not dependent on polycomb group proteins or DNA methylation. Thus, the mechanism by which Airn silences Igf2r, the only gene in this cluster with an essential embryonic function, remains unknown.”

Since Airn transcription overlaps the Igf2r promoter, but not the promoter of Slc22a3 or Slc22a2, that silencing could depend on Airn transcription overlap and not the Airn lncRNA product.

“To test whether Airn transcription or product silences the Igf2r gene, we shortened the endogenous lncRNA to different lengths,” the investigators wrote. “The results excluded a role for spliced and unspliced Airn lncRNA products and for Airn nuclear size and location in silencing Igf2r. Instead, silencing only required Airn transcriptional overlap of the Igf2r promoter, which interferes with RNA polymerase II recruitment in the absence of repressive chromatin.”

The findings collectively reflect “hallmark features” of macro lncRNAs, such as inefficient splicing, extreme length, high repeat content, lack of conservation, and short half-life, all of which point to transcription as more important than product, the investigators concluded.

“It is not yet known how many of the growing number of mammalian lncRNAs share these hallmarks,” they stated. “If they do, the range of lncRNA functions in the mammalian genome could be substantially enlarged.”

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