Wang, K.C. et al (in 2011) were the first to identify the HOTTIP lncRNAs.

HOTTIP, a lincRNA is transcribed from the 5′ tip of the HOXA locus that coordinates the activation of multiple 5′HOXA genes in vivo. Chromosomal looping brings HOTTIP into close proximity to its target genes. It is cis-lncRNAs or also called as the cis-acting RNAs, that regulate the expression of genes in close genomic proximity.

HOXA genes  (from an abbreviation of homeobox) are a group of related genes that control the body plan of the embryo along the anterior-posterior (head-tail) axis in vivo. HOTTIP directly binds the adaptor protein WDR5 and targets WDR5/MLL complexes across HOXA, driving histone H3 lysine 4 trimethylation and gene transcription.

When HOTTIP was knocked down, the proteins MLL1 and WDR5 were not observed on the transcription start sites of HOX5 genes as they normally are. However, these effects could not be rescued by expressing HOTTIP from another region on the genome, indicating that the lncRNA must work from the chromosome on which it is transcribed (cis-acting). Indeed, chromosome conformation capture techniques have indicated that chromatin looping brings the RNA into close proximity to the activated genes.

HOTTIP lincRNA is transcribed in opposite orientation to the genes in the HOXA locus. Its start site is located 300 bp upstream from the 5′ end of the HOXA cluster (Sònia Guil& Manel Esteller 2012 review)


Screenshot - 06102013 - 06:02:15 PM


HOTTIP RNA is able to interact directly with the SET domain–containing lysine methyltransferase WDR5–MLL complexes, and its depletion reduces WDR5 occupancy across the HoxA cluster, again with a more prominent effect near the 5′ end of the cluster. This is coincident with a loss of the histone H3 Lys4-trimethyl activating mark (H3K4me3) so that HOTTIP RNA acts by facilitating H3K4me3 deposition and activating transcription of the region (above figure). Ectopic expression of HOTTIP fails to mimic these effects, suggesting it is a cis-acting LncRNA

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