The sequence, structure and evolutionary features of HOTAIR in mammals

Abstract

BackgroundAn increasing number of long noncoding RNAs (lncRNAs) have been identified recently. Different from all the others that function in cis to regulate local gene expression, the newly identified HOTAIR is located between HoxC11 and HoxC12 in the human genome and regulates HoxD expression in multiple tissues. Like the well-characterised lncRNA Xist, HOTAIR binds to polycomb proteins to methylate histones at multiple HoxD loci, but unlike Xist, many details of its structure and function, as well as the trans regulation, remain unclear. Moreover, HOTAIR is involved in the aberrant regulation of gene expression in cancer.ResultsTo identify conserved domains in HOTAIR and study the phylogenetic distribution of this lncRNA, we searched the genomes of 10 mammalian and 3 non-mammalian vertebrates for matches to its 6 exons and the two conserved domains within the 1800 bp exon6 using Infernal. There was just one high-scoring hit for each mammal, but many low-scoring hits were found in both mammals and non-mammalian vertebrates. These hits and their flanking genes in four placental mammals and platypus were examined to determine whether HOTAIR contained elements shared by other lncRNAs. Several of the hits were within unknown transcripts or ncRNAs, many were within introns of, or antisense to, protein-coding genes, and conservation of the flanking genes was observed only between human and chimpanzee. Phylogenetic analysis revealed discrete evolutionary dynamics for orthologous sequences of HOTAIR exons. Exon1 at the 5' end and a domain in exon6 near the 3' end, which contain domains that bind to multiple proteins, have evolved faster in primates than in other mammals. Structures were predicted for exon1, two domains of exon6 and the full HOTAIR sequence. The sequence and structure of two fragments, in exon1 and the domain B of exon6 respectively, were identified to robustly occur in predicted structures of exon1, domain B of exon6 and the full HOTAIR in mammals.ConclusionsHOTAIR exists in mammals, has poorly conserved sequences and considerably conserved structures, and has evolved faster than nearby HoxC genes. Exons of HOTAIR show distinct evolutionary features, and a 239 bp domain in the 1804 bp exon6 is especially conserved. These features, together with the absence of some exons and sequences in mouse, rat and kangaroo, suggest ab initio generation of HOTAIR in marsupials. Structure prediction identifies two fragments in the 5' end exon1 and the 3' end domain B of exon6, with sequence and structure invariably occurring in various predicted structures of exon1, the domain B of exon6 and the full HOTAIR.

Evolutionary annotation of conserved long non-coding RNAs in major mammalian species

“…The pair-wise conservation atlases of each chromosome for human lncRNA genes also exhibit the same pattern ( Figure 2b; Figure S5). Consistent with the reported studies [39,40], hotair were found widely existing in mammals, as shown by the CPCC score in PhyloNONCODE ( Figure S11), and the xist gene existing from humans to the opossum, absent in the platypus and chicken ( Figure S11). 62% and 59% of human lncRNAs were found to be 1 : 1 orthologous in mouse and rat with CPCC score in 0 to 1, similar to a study of human long non-coding RNAs in the other six mammals, in which the figures are 58% and 54% [26].…”

Dysregulated Expression of Long Noncoding RNAs in Ovarian Cancer

“…10Y12 lncRNAs have also been related to many diverse biological processes, such as cell cycle, cell proliferation, cell apoptosis, and cell differentiation. 17Y19 On the basis of the pattern of their functions, lncRNAs have been divided into 4 subtypes, namely, signals (X-inactive specific transcript [XIST] 20 and PANDA 21 ), decoys (Gas5 21 ), guides (HOX transcript antisense intergenic RNA [HOTAIR] 22 and lincRNA-p21 23 ), and scaffolds (Anril 24 ). Previous studies have found that the abnormal expression or dysfunction of lnRNA is closely related to the initiation and progression of human diseases, including cancer.…”

“…23,24 The human HOX gene family is divided into 4 subfamilies: HOXA, HOXB, HOXC, and HOXD, whereas LncRNA HOTAIR is identified from a custom tilling array of the HOXC locus. 25,26 HOTAIR is located in the antisense strand of the HOXC gene cluster, but it could regulate the HOXD gene cluster.…”

HOTAIR: a cancer-related long non-coding RNA

“…Structure prediction vertified that the sequences and structures of the 5' end exon 1 and the 3' end domain B of exon 6 were highly conserved in mammals. It is considered that the two domains are the functional domains of HOTAIR, which can interact with polycomb protein and play a wide range of biological functions [54].…”