Control of somatic tissue differentiation by the long non-coding RNA TINCR

By M. Kretz, Z. Siprashvili, Ci Chu, Dan E. Webster, Ashley M. Zehnder, Kun Qu, Carolyn S. Lee, R. Flockhart, A. Groff, Jennifer M. Chow and 10 more. Nature, 2012

910 citations recorded by the source corpus.

Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized; 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.

Subfields: Cancer Research, Endocrinology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/05bb20de1a3177b4be76e0849a2867385a9d87e5

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Citations in the corpus

Long noncoding RNAs: Cellular address codes in development and disease (2013, positive): “TINCR localizes to the cytoplasm, where it interacts with Staufen 1 protein (STAU1) to promote the stability of mRNAs containing the TINCR box motif (Kretz et al., 2013) (Figure 4A).”
Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution (2015, background): “More recently, researchers have developed and applied single molecule RNA FISH techniques based on hybridization of multiple short, fluorescently labeled, oligonucleotide probes [23,24] to estimate the absolute level and subcellular localization of even low abundance lncRNAs [8,25-31].”
CRISPRi-based genome-scale identification of functional long non-coding RNA loci in human cells (2016, neutral): “Our study, which focused on lncRNAs required for robust cell growth, underestimates the true number of functional lncRNAs in these cell types, as lncRNAs have been shown to regulate more evolutionarily complex cellular decisions such as cell fate (7, 19, 57, 58), cancer metastasis (59, 60), and perh”
MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA–DNA triplex structures (2015, neutral): “Black in the EZH2 bar indicates the number of T-to-C transitions (1,253) that are either present in input or H3K27me3 samples, and blue indicates EZH2-specific T-to-C transitions (17,652).”
The rise of regulatory RNA (2014, background): “These include, based on studies in cell culture, the regulation of apoptosis and metastatic processes 211,218,220,221,234 , retinal and erythroid development 211,235 , breast development 210,236 , and epidermal differentiation 237 , among many others.”
Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA (2017, background): “It is of note that the lncRNA terminal differentiation-induced ncRNA (TINCR) also recruits STAU1 to mRNAs such as the one encoding peptidoglycan recognition protein 3 (PGLYRP3) in epidermis [61].”
Non-coding RNAs in Development and Disease: Background, Mechanisms, and Therapeutic Approaches. (2016, background): “7 kb in size and is highly enriched in the cytoplasma of keratinocytes (144).”