Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized1–4; however, potential roles for lncRNAs in somatic tissue differentiation remain poorly understood. Here we show that a 3.7-kilobase lncRNA, terminal differentiation-induced ncRNA (TINCR), controls human epidermal differentiation by a post-transcriptional mechanism. TINCR is required for high messenger RNA abundance of key differentiation genes, many of which are mutated in human skin diseases, including FLG, LOR, ALOXE3, ALOX12B, ABCA12, CASP14 and ELOVL3. TINCR-deficient epidermis lacked terminal differentiation ultrastructure, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs. TINCR–mRNA interaction occurs through a 25-nucleotide ‘TINCR box’ motif that is strongly enriched in interacting mRNAs and required for TINCR binding. A high-throughput screen to analyse TINCR binding capacity to approximately 9,400 human recombinant proteins revealed direct binding of TINCR RNA to the staufen1 (STAU1) protein. STAU1-deficient tissue recapitulated the impaired differentiation seen with TINCR depletion. Loss of UPF1 and UPF2, both of which are required for STAU1-mediated RNA decay, however, did not have differentiation effects. Instead, the TINCR–STAU1 complex seems to mediate stabilization of differentiation mRNAs, such as KRT80. These data identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression.

Many studies are uncovering functional roles for long noncoding RNAs (lncRNAs), yet few have been tested for in vivo relevance through genetic ablation in animal models. To investigate the functional relevance of lncRNAs in various physiological conditions, we have developed a collection of 18 lncRNA knockout strains in which the locus is maintained transcriptionally active. Initial characterization revealed peri- and postnatal lethal phenotypes in three mutant strains (Fendrr, Peril, and Mdgt), the latter two exhibiting incomplete penetrance and growth defects in survivors. We also report growth defects for two additional mutant strains (linc–Brn1b and linc–Pint). Further analysis revealed defects in lung, gastrointestinal tract, and heart in Fendrr−/− neonates, whereas linc–Brn1b−/− mutants displayed distinct abnormalities in the generation of upper layer II–IV neurons in the neocortex. This study demonstrates that lncRNAs play critical roles in vivo and provides a framework and impetus for future larger-scale functional investigation into the roles of lncRNA molecules.DOI: http://dx.doi.org/10.7554/eLife.01749.001

Long noncoding RNAs (lncRNAs) have been implicated in numerous cellular processes including brain development. However, the in vivo expression dynamics and molecular pathways regulated by these loci are not well understood. Here, we leveraged a cohort of 13 lncRNAnull mutant mouse models to investigate the spatiotemporal expression of lncRNAs in the developing and adult brain and the transcriptome alterations resulting from the loss of these lncRNA loci. We show that several lncRNAs are differentially expressed both in time and space, with some presenting highly restricted expression in only selected brain regions. We further demonstrate altered regulation of genes for a large variety of cellular pathways and processes upon deletion of the lncRNA loci. Finally, we found that 4 of the 13 lncRNAs significantly affect the expression of several neighboring proteincoding genes in a cis-like manner. By providing insight into the endogenous expression patterns and the transcriptional perturbations caused by deletion of the lncRNA locus in the developing and postnatal mammalian brain, these data provide a resource to facilitate future examination of the specific functional relevance of these genes in neural development, brain function, and disease.T he exquisite complexity of the mammalian brain derives from its vast diversity of neuronal and glial cell types (1, 2). The specification and differentiation of such a variety of cell types during brain development is finely orchestrated spatiotemporally by the regulation of complex transcriptional programs. Increasing evidence points to a role for long noncoding RNAs (lncRNAs) as key regulatory elements of this process. Intriguingly, within the mammalian body, the largest repertoire and diversity of lncRNA genes outside the germ line occurs in the brain (3-10), where lncRNAs exhibit regional and cell-specific localization (6, 10). Although many unanswered questions remain regarding the functional activity and molecular mechanisms of lncRNA loci, the expression patterns of lncRNAs may serve as a proxy signal for important, context-specific biological activity.A role for lncRNA genes in brain development and function is supported by the fact that ablation of two lncRNA loci, Evf2 and Pantr2 (linc-Brn1b), perturbs neuronal development (11, 12). Loss of Evf2, a developmentally regulated lncRNA that controls transcriptional activity through cooperation with the homeodomain protein DLX-2 (11), leads to abnormal development and synaptic function of hippocampal GABAergic interneurons (11). Similarly, ablation of the Pantr2 locus results in a decreased number of intermediate progenitors in the developing telencephalon, reduced neurons in L2/3 of the cerebral cortex, and disorganization of the barrel cortex (12). Furthermore, human genetic studies have pointed to lncRNAs as potential factors in brain disorders (10,(13)(14)(15)(16).To gain preliminary insights into the functional and physiological relevance of lncRNA loci in vivo, we previously generated knockout (KO) mouse models of ...