HOTAIR (for
HOX transcript
antisense RNA
Antisense RNA (asRNA), also referred to as antisense transcript, natural antisense transcript (NAT) or antisense oligonucleotide, is a single stranded RNA that is complementary to a protein coding messenger RNA (mRNA) with which it hybridizes, and ...
) is a human
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
located between HOXC11 and HOXC12 on
chromosome 12. It is the first example of an RNA expressed on one chromosome that has been found to influence the
transcription of the HOXD cluster posterior genes located on chromosome 2. The sequence and function of HOTAIR are different in humans and mice. Sequence analysis of HOTAIR revealed that it exists in mammals, has poorly conserved sequences and considerably conserved structures, and has evolved faster than nearby HoxC genes. A subsequent study identified HOTAIR has 32 nucleotides long conserved noncoding element (
CNE) that has a paralogous copy in HOXD cluster region (located between HOXD11 and HOXD12),
suggesting that the HOTAIR conserved sequences predate whole genome duplication events at the root of vertebrate. While the conserved sequence paralogous with HOXD cluster is 32 nucleotide long, the HOTAIR sequence conserved from human to fish is about 200 nucleotide long and is marked by active enhancer features (bidirectional transcription,
H3K4me1 and
H3K27ac peaks).
Gene and transcribed RNA product
The HOTAIR gene contains 6,232
bp and encodes a 2.2 kb
long noncoding RNA molecule, which controls gene expression. Its source
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
is located within a
HOXC gene cluster
A gene cluster is a group of two or more genes found within an organism's DNA that encode similar peptide, polypeptides or proteins which collectively share a generalized function and are often located within a few thousand base pairs of each othe ...
. It is shuttled from chromosome 12 to chromosome 2 by the
Suz-Twelve protein.
Function
The
5′ end of HOTAIR interacts with a
Polycomb-group protein Polycomb Repressive Complex 2 (
PRC2) and as a result regulates
chromatin
Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...
state. It is required for gene-silencing of the
HOXD locus by PRC2.
PRC2 is dispensable for HOTAIR-mediated transcriptional silencing. The
3′ end of HOTAIR interacts with the
histone demethylase
Demethylases are enzymes that remove methyl (CH3) groups from nucleic acids, proteins (particularly histones), and other molecules. Demethylases are important epigenetics, epigenetic proteins, as they are responsible for transcriptional regulation ...
LSD1.
It is an important factor in the
epigenetic differentiation of skin over the surface of the body. Skin from various anatomical positions is distinct, e.g. the skin of the eyelid differs markedly from that on the sole.
Clinical significance
HOTAIR is highly expressed in
metastatic breast cancers. High levels of expression in primary breast tumours are a significant predictor of subsequent metastasis and death. This is partially due to HOTAIR-mediated
overexpression of the
HER2 oncogene through sequestration of miR-331-3p, which is a
negative regulator of HER2 expression. In cells, especially those that over express
PRC2, the prevention of HOTAIR expression leads to a reduction in invasive potential of that cell.
It is also involved in
esophageal squamous cell carcinoma.
References
Further reading
*
*
*
*
*
*
*
*
External links
*
*
*
*
*
Antisense RNA
Non-coding RNA
{{gene-12-stub