The Discovery and Characterization of the lncRNA Firre

Abstract

RNAs, including long noncoding RNAs (lncRNA), are known to be abundant and important structural components of the nuclear infrastructure. Yet, the identities, functional roles, and localization dynamics of lncRNAs that influence nuclear architecture remain poorly understood. Another unexplored territory is the molecular nature of the nuclear lncRNAs, which hampers a mechanistic understanding of how these RNAs establish proper epigenetic states and drive and modulate nuclear compartmentalization. Here, we identify a lncRNA that we discovered and termed Functional Intergenic RNA Repeat Element (Firre). Firre is a strictly nuclear lncRNA that interacts with the nuclear matrix protein hnRNPU, through a 156 bp repeat motif in its mature transcript sequence. This conserved and unique repeat motif, Repeating RNA Domain (RRD), is not only necessary to localize Firre around its site of transcription in the nucleus but also sufficient to act as a nuclear localization signal for any RNA in a species-specific manner. Furthermore, Firre spreads across a ~5 Megabase (Mb) domain around its transcription site on the X chromosome and localizes across at least five distinct trans-chromosomal loci in the genome. The trans-chromosomal targets reside in spatial proximity to the Firre locus, the genetic deletion of which results in the loss of co-localization of these trans-chromosomal interacting loci. Interestingly, the knockdown of hnRNPU also impedes these trans sites to be brought into the vicinity of the Firre locus. Thus, our data suggest a new form of lncRNA-mediated regulation in the nucleus, in which lncRNAs, such as Firre, via their unique repetitive domains, can interface with and modulate nuclear architecture across chromosomes.