A Keystone for ncRNA

A report on the Keystone symposium 'Non-coding RNAs' held at Snowbird, Utah, USA, 31 March to 5 April 2012.Molecular and Cellular BiologyStem Cell and Regenerative Biolog

Function and evolution of local repeats in the Firre locus

More than half the human and mouse genomes are comprised of repetitive sequences, such as transposable elements (TEs), which have been implicated in many biological processes. In contrast, much less is known about other repeats, such as local repeats that occur in multiple instances within a given locus in the genome but not elsewhere. Here, we systematically characterize local repeats in the genomic locus of the Firre long noncoding RNA (lncRNA). We find a conserved function for the RRD repeat as a ribonucleic nuclear retention signal that is sufficient to retain an otherwise cytoplasmic mRNA in the nucleus. We also identified a repeat, termed R0, that can function as a DNA enhancer element within the intronic sequences of Firre. Collectively, our data suggest that local repeats can have diverse functionalities and molecular modalities in the Firre locus and perhaps more globally in other lncRNAs

Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer

Mounting evidence suggests that long noncoding RNAs (lncRNAs) can function as microRNA sponges and compete for microRNA binding to protein-coding transcripts. However, the prevalence, functional significance and targets of lncRNA-mediated sponge regulation of cancer are mostly unknown. Here we identify a lncRNA-mediated sponge regulatory network that affects the expression of many protein-coding prostate cancer driver genes, by integrating analysis of sequence features and gene expression profiles of both lncRNAs and protein-coding genes in tumours. We confirm the tumour-suppressive function of two lncRNAs (TUG1 and CTB-89H12.4) and their regulation of PTEN expression in prostate cancer. Surprisingly, one of the two lncRNAs, TUG1, was previously known for its function in polycomb repressive complex 2 (PRC2)-mediated transcriptional regulation, suggesting its sub-cellular localization-dependent function. Our findings not only suggest an important role of lncRNA-mediated sponge regulation in cancer, but also underscore the critical influence of cytoplasmic localization on the efficacy of a sponge lncRNA

Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre

RNA, including long noncoding RNA (lncRNA), is known to be an abundant and important structural component of the nuclear matrix. However, the molecular identities, functional roles and localization dynamics of lncRNAs that influence nuclear architecture remain poorly understood. Here, we describe one lncRNA, Firre, that interacts with the nuclear-matrix factor hnRNPU through a 156-bp repeating sequence and localizes across an ~5-Mb domain on the X chromosome. We further observed Firre localization across five distinct trans-chromosomal loci, which reside in spatial proximity to the Firre genomic locus on the X chromosome. Both genetic deletion of the Firre locus and knockdown of hnRNPU resulted in loss of colocalization of these trans-chromosomal interacting loci. Thus, our data suggest a model in which lncRNAs such as Firre can interface with and modulate nuclear architecture across chromosomes

The Discovery and Characterization of the lncRNA Firre

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.Biology, Molecular and Cellula

Long noncoding RNAs regulate adipogenesis

The prevalence of obesity has led to a surge of interest in understanding the detailed mechanisms underlying adipocyte development. Many protein-coding genes, mRNAs, and microRNAs have been implicated in adipocyte development, but the global expression patterns and functional contributions of long noncoding RNA (lncRNA) during adipogenesis have not been explored. Here we profiled the transcriptome of primary brown and white adipocytes, preadipocytes, and cultured adipocytes and identified 175 lncRNAs that are specifically regulated during adipogenesis. Many lncRNAs are adipose-enriched, strongly induced during adipogenesis, and bound at their promoters by key transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα). RNAi-mediated loss of function screens identified functional lncRNAs with varying impact on adipogenesis. Collectively, we have identified numerous lncRNAs that are functionally required for proper adipogenesis.National Institutes of Health (U.S.). (Grant DK047618)National Institutes of Health (U.S.). (Grant DK068348)National Institutes of Health (U.S.). (Grant 5P01HL066105)National Science Foundation (U.S.) (Postdoctoral Fellowship