User:Kinkreet/MGE/A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression

Long intergenic noncoding RNAs (lincRNAs) have shown to be involved in gene silencing, possibly through methylation of histones. They are involved in the regulation of homeostasis and development

Homeotic genes are genes in which their differential expression determines the segmentation of different body parts. In vertebrates, there are 39 genes, clustered into 4 loci; at the anterior and proximal end of the organism, genes at the 3' end of the cluster is highly expressed relative to the 5' end; and at the posterior and distal end, genes at the 5' end are expressed more. This close resemblance of the location of the gene relative to the expression level at the axis of the organism is known as colinearity.

At the 5' end of the HOXA locus (one of the 4 clusters), a lincRNA called HOTTIP is transcribed and appears to activate gene expression of neighboring genes at the 5' end of HOXA in vivo, by looping the chromosome so that HOTTIP is in close proximity to the target genes. The HOTTIP lincRNA binds to an adapter protein WDR5, which complexes with WDR5/MLL and drives histone H3 lysine 4 trimethylation and gene transcription. The proximity of the HOTTIP to the target gene is essential for their activation. These data suggests that lincRNAs have roles in both the silencing and activation of genes, and that it may mediate long-range regulatory effects.

Chromosome structure and histone modifications human primary fibroblasts were studied using high-throughput chromosome conformation capture-carbon copy (5C), and found that fibroblasts at the distal areas (foreskin and foot) expressed genes closer to the 5' end of the cluster, whereas the 3' end is silenced. Proximal fibroblasts showed the opposite results, with high expression at the 3' end and silent at the 5' end. This switching on and off of genes are mediated by MLL/Trithorax (Trx) and polycomb group (PcG) proteins, which trimethylates histone H3 at lysine 4 (H3K4me3) to activate genes, or at lysine 27 (H3K27me3) to repress genes. In the actively-transcribed regions, many looping structures were observed, and the DNA is densely packed; in contrast, the DNA at the silent regions are mostly linear and lack looping structures.

The HOXA loci is flanked by two lincRNAs - myelopoiesisassociated lincRNA (HOTAIRM1) at the 3' end, and HOXA transcript at the distal tip (HOTTIP) for the 5' end. The HOTTIP loci is transcribed as a 3,764-nucleotide, spliced and polyadenylated lincRNA.