Biology:HOTAIR

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Short description: Gene found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


HOTAIR (for HOX transcript antisense RNA)[1] is a human gene 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 transcription of HOXD cluster posterior genes located on chromosome 2. The sequence and function of HOTAIR is different in human and mouse.[2] 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.[3] A subsequent study identified HOTAIR has 32 nucleotide long conserved noncoding element (CNE) that has a paralogous copy in HOXD cluster region (located between HOXD11 and HOXD12),[4] suggesting that the HOTAIR conserved sequences predates 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).[4]

Gene and transcribed RNA product

The HOTAIR gene contains 6,232 bp and encodes 2.2 kb long noncoding RNA molecule, which controls gene expression. Its source DNA is located within a HOXC gene cluster. It is shuttled from chromosome 12 to chromosome 2 by the Suz-Twelve protein.[5]

Function

The 5′ end of HOTAIR interacts with a Polycomb-group protein Polycomb Repressive Complex 2 (PRC2) and as a result regulates chromatin state. It is required for gene-silencing of the HOXD locus by PRC2.[6][7] PRC2 is dispensable for HOTAIR-mediated transcriptional silencing.[8] The 3′ end of HOTAIR interacts with the histone demethylase LSD1.[7]

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 of the foot.[6][9]

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.[10] In cells, especially those that over express PRC2, the prevention of HOTAIR expression leads to a reduction in invasive potential of that cell.[11] It is also involved in esophageal squamous cell carcinoma.[12]

References

  1. ↑ "Genecards entry on HOTAIR". https://www.genecards.org/cgi-bin/carddisp.pl?gene=HOTAIR. 
  2. ↑ "Structural and functional differences in the long non-coding RNA hotair in mouse and human". PLOS Genetics 7 (5): e1002071. May 2011. doi:10.1371/journal.pgen.1002071. PMID 21637793. 
  3. ↑ "The sequence, structure and evolutionary features of HOTAIR in mammals". BMC Evolutionary Biology 11 (1): 102. April 2011. doi:10.1186/1471-2148-11-102. PMID 21496275. Bibcode: 2011BMCEE..11..102H. 
  4. ↑ 4.0 4.1 "Ancestrally Duplicated Conserved Noncoding Element Suggests Dual Regulatory Roles of HOTAIR in cis and trans" (in English). iScience 23 (4): 101008. April 2020. doi:10.1016/j.isci.2020.101008. PMID 32268280. Bibcode: 2020iSci...23j1008N. 
  5. ↑ "Genetics: The production line". Nature 454 (7208): 1042–5. August 2008. doi:10.1038/4541042a. PMID 18756228. 
  6. ↑ 6.0 6.1 "Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs". Cell 129 (7): 1311–23. June 2007. doi:10.1016/j.cell.2007.05.022. PMID 17604720. 
  7. ↑ 7.0 7.1 "Long noncoding RNA as modular scaffold of histone modification complexes". Science 329 (5992): 689–93. August 2010. doi:10.1126/science.1192002. PMID 20616235. Bibcode: 2010Sci...329..689T. 
  8. ↑ "PRC2 is dispensable for HOTAIR-mediated transcriptional repression". The EMBO Journal 36 (8): 981–994. April 2017. doi:10.15252/embj.201695335. PMID 28167697. 
  9. ↑ "Homeobox genes, fetal wound healing, and skin regional specificity". The Journal of Investigative Dermatology 120 (1): 9–11. January 2003. doi:10.1046/j.1523-1747.2003.00002.x. PMID 12535191. 
  10. ↑ "Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer". Molecular Cancer 13: 92. April 2014. doi:10.1186/1476-4598-13-92. PMID 24775712. 
  11. ↑ "Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis". Nature 464 (7291): 1071–6. April 2010. doi:10.1038/nature08975. PMID 20393566. Bibcode: 2010Natur.464.1071G. 
  12. ↑ "Upregulation of the long non-coding RNA HOTAIR promotes esophageal squamous cell carcinoma metastasis and poor prognosis". Molecular Carcinogenesis 52 (11): 908–15. November 2013. doi:10.1002/mc.21944. PMID 24151120. 

Further reading

External links




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