LÄHDE:
https://www.nature.com/articles/nature11661
Abstract
Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized1,2,3,4;
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.
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