HOTAIR - a cancer lincRNA


We start with HOTAIR, because it was discovered by one of our ex- collaborators and, even more importantly, he chose a name that we like [see below].

HOTAIR is a long intergenic noncoding RNA (lincRNA). The name HOTAIR stands for ‘HOX antisense intergenic RNA’, or does it really?

From the article linked above:

As Popular Science notes, “[Rinn] silenced his critics in 2007 when he showed that one of the [lincRNA molecules] serves a vital function in human cells. He dubbed it HOTAIR, a wry nod to the fact that so many scientists thought his field of research was full of it. The molecule delivers proteins to a crucial cluster of genes and helps regulate immune response, cancer growth and fat- and stem-cell production, among other things.”

Biological Role

HOTAIR interacts with chromatin remodeling complexes to help them target specific genes or genomic regions. HOTAIR is found to repress genes in HOXD complex. Regarding its specific functionality, so far it appears that HOTAIR likely acts as a bridge or scaffold to bring two protein complexes together, namely Polycomb Repressive Complex 2 (PRC2) and histone demethylase LSD1.

HOTAIR is the first lincRNA found to be trans-acting. What does that mean? It implies that HOTAIR is located in one chromosome (chromosome 12 of human genome) and works on a different chromosome (chromosome 2). Suz-Twelve protein carries HOTAIR from chromosome 12 to chromosome 2.

HOTAIR is an oncogenic lincRNA and has been linked with breast cancer metastasis.

Chain of key discoveries

Tiling array map of chromosome 22

In 2003, John Rinn and his colleagues at Yale published a tiling-array study of a human chromosome - _The transcriptional activity of human Chromosome 22_. It was not the first tiling array map of chromosome 22, because a group from Affy published a similar map few months earlier. However, Rinn’s approach had few strengths that helped him in later experiments. He used maskless array synthesizer technology later commercialized by Nimblegen. With maskless array synthesizer, the cost of redesigning arrays is minimal. So, one can make an array of any region of chromosome he wishes with any density, and pop comes out an array from the machine. The cost of designing the mask was prohibitive for Affymetrix.

Tiling array map of entire human genome

In 2004, a collaborative team of scientists from Yale and NASA Ames (including one of us) published similar map of the entire human genome - _Global Identification of Human Transcribed Sequences with Genome Tiling Arrays_. For a free copy of the article, check here. Using maskless array technology was the main reason for this team to perform the experiment so rapidly.

Dense tiling array map of human Hox cluster

John Rinn moved to Stanford to work with Howard Chang and designed another highly dense maskless array (5 nucleotide resolution) to check the Hox cluster. The result was fascinating. They found 231 ncRNAs and one of them named HOTAIR was found to be involved in gene silencing at a distance. Their study was published in Cell - _Functional Demarcation of Active and Silent Chromatin Domains in Human HOX Loci by Noncoding RNAs_.

Link with cancer

Chang lab continued to work on HOTAIR. In 2010, they published two interesting studies. In the first paper - _Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis_ - they linked HOTAIR with cancer metastasis.

In the second paper, they reported that HOTAIR interacts with histone modification complex LSD1 - _Long Noncoding RNA as Modular Scaffold of Histone Modification Complexes_

Useful information and links

Location

Chr12

Size

6,232 nt on chromosome, 2.2 Kbp exons.

Sequence

Link

Function

Silencing - control transcription of chr 2

Bridging of PRC2 and LSD1 complexes

Wiki

Link


Written by M. //

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