Silencing by the imprinted Airn macro lncRNA

The majority of the mammalian genome is transcribed into long non-coding (lnc) RNAs, transcripts longer than 200 nucleotides and devoid of protein-coding potential. Recent genome-wide mapping efforts led to the identification of thousands novel lncRNAs, but so far only few have been functionally analyzed. Fifteen years ago, our group discovered Airn (antisense to Igf2r RNA non-coding), the first autosomal lncRNA shown to have a silencing function. Airn is an imprinted gene transcribed from the paternal chromosome, in antisense orientation to the imprinted but maternally expressed Igf2r gene. Airn expression controls Igf2r imprinted expression by silencing it in cis on the paternal chromosome, but how Airn exerts its silencing function has long been a mystery. Now, a study published in Science shows that Airn silences Igf2r through transcription alone and not via its RNA product. The road leading to this discovery was long and winding. When we first identified Airn and deleted its expressed, paternal promoter, we observed de-repression of the normally silent paternal Igf2r allele. After this landmark experiment, three hypotheses were formulated to explain how Airn may silence Igf2r: (1) the Airn promoter competes with the Igf2r promoter for common transcription factors or enhancers; (2) the Airn lncRNA coats the paternal chromosome, inducing its heterochromatization; (3) Airn transcription through the Igf2r promoter interferes with its expression. The promoter competition model was ruled out some years later by an experiment that prematurely terminated the 118 kb-long Airn transcript by Silencing by the imprinted Airn macro lncRNA Transcription is the answer