Genome-wide sequencing studies across 24 human tissues and cell types have revealed that lncRNAs are exquisitely tissue-specific, even more so than protein-coding genes 34 High throughput sequencing of specific tissues and cellular lineages have been performed in the blood 94; 95, pancreas 96, adipocytes 97, and adult and embryonic cerebral cortex 98. A high-throughput siRNA study of lncRNAs in ESCs revealed particular transcripts can repress the differentiation into each of the germ layers 99. In addition, lncRNAs can be bound by both pluripotency and lineage-specific transcription factors 100. This suggests a model whereby lncRNAs can play key roles in both the fate specification and differentiation of cell types throughout the body.
Lnc-MD1 is a muscle-specific transcript that is induced upon myoblast differentiation into myocytes (101). Lnc-MD1 acts as a microRNA ‘sponge’ for miR-133 and miR- 135, which allows for the upregulation of muscle-specific transcription factors. Interestingly, lnc-MD1 also serves as the host transcript for miR-133, and participates in a feed-forward regulatory loop with RNA-binding protein-HuR 102. HuR is negatively regulated by miR-133, but binds and stabilizes lnc-MD1, thereby causing additional ‘sponging,’ lower miR14 133 biosyntheses, and an increase in HuR levels. Through miRNA sponging and regulation of HuR, a single lncRNA transcript can control the timing of skeletal muscle differentiation 102.
In the skin, two lncRNAs with opposing roles in progenitor differentiation have been identified. LncRNA ANCR expression is strongly enriched in skin progenitor populations and becomes downregulated during differentiation 107. Depletion of this lncRNA causes rapid gene expression changes, consistent with differentiation as well as ectopic differentiation of progenitors in an organotypic cell culture system. In contrast, the lncRNA TINCR becomes induced upon progenitor differentiation, and its depletion causes a loss of differentiated cell types 108. TINCR interact with STAUFEN-1 and several pro-differentiation mRNAs to promote their stability 108.
In the blood lineage, two lncRNAs have been investigated that are essential for proper differentiation and functioning of dendritic cells. LincRNA Cox2 is induced by immunogenic stimuli and regulates the expression of key cytokines 109. This action achieved at least in part through its interaction with HnRNP A/B and HnRNP A2/B1, RNA binding proteins with known roles in transcriptional activation and splicing. Another example is Lnc-DC1, which is specifically induced during monocyte differentiation into dendritic cells. Depletion of this transcript causes both a loss of proper differentiation and an inability to respond to immunogenic stimuli 83. Lnc-DC1 is a predominantly cytoplasmic lncRNA that functions through modulating the phosphorylation state and therefore nuclear translocation of STAT3 83.
LncRNAs therefore play fundamental roles in both the differentiation and function of a key immune cell type.