A Conversation with Ling-Ling Chen.

Dr. Chen: I wouldn’t call it a switch, but really a smooth transition. Ten years ago, one of the most exciting discoveries in molecular biology was pervasive transcription of the genome, leading to the discovery of intergenic-regiontranscribed long noncoding RNAs [lincRNAs]. We know that the transcription and processing of long noncoding RNAs is different from those of mRNAs [messenger RNAs], but at the ends these mature lncRNAs look similar to mRNAs: They have 5′ mG-capping or 3′ poly(A) tails with only a few exceptions, like NEAT1 [Nuclear Enriched Abundant Transcript 1] or MALAT1 [Metastasis-Associated Lung Adenocarcinoma Transcript 1], originally discovered by Dave Spector’s lab right here at Cold Spring Harbor. His lab found that the 3′-end processing of these two basically used an RNase P cleavage related to tRNA [transfer RNA] biogenesis, and those RNAs look so different at the 3′ ends from mRNAs. Luckily, I worked on NEAT1 with Gordon Carmichael at the time. Starting from those Alu elements, I found that mRNAs containing inverted Alu repeats are preferentially retained in the nuclei in bodies called paraspeckles. I found that NEAT1 is a major organizer of paraspeckles. So, triggered by the very interesting, different appearance of NEAT1, I asked the question: Do all RNAs look the same as mRNAs? From there, I began to explore the nonpoly(A) transcriptome, which had been ignored by so many people as just junk. We discovered different classes of previously unknown species. These RNAs do not have their own promoters, but rather are processed from the primary Pol II [RNA Polymerase II] transcripts and then stabilized by distinct mechanisms like forming RNA circles, or by the protection of snoRNP [small nucleolar RNA–protein] complexes at one or both ends. More importantly, now we’ve figured out that some of them can impact important functions of gene regulation in cells that also relate to human diseases including Prader–Willi syndrome and autoimmune diseases like lupus. We’re happy to see that these previously thought-of-as-junk things can do something in cells.