HOXA11-AS lncRNA is a long non-coding RNA from the antisense strand in the homeobox A (HOXA gene). The HOX gene contains four clusters (A, B, C, and D). The sense strand of the HOXA gene codes for proteins. Alternative names for HOXA11-AS lncRNA are: HOXA-AS5, HOXA11S, HOXA11-AS1, HOXA11AS, or NCRNA00076. This gene is 3,885 nucleotides long and resides at chromosome 7 (7p15.2) and is transcribed from an independent gene promoter. Being a lncRNA, it is longer than 200 nucleotides in length, in contrast to regular non-coding RNAs.
The HOX genes code for transcription factors that are key to embryonic development. This lncRNA is one of the three lncRNAs present in the 5-prime region of the HOXA11 gene. The other two lncRNAs are HOXA10-AS and HOTTIP. Of these lncRNAs, HOXA11-AS, is the most conserved sequence in a wide range of organisms, which shows its longevity in the phylogenetic tree. Since HOX genes play a prominent role in embryogenesis and carcinogenesis, genes on the sense strand and antisense non-coding RNA (ncRNA) genes are often studied in their role of aberrant epithelial differentiation and cancer development.
Function
Many lncRNAs are sequences that regulate the expression of nearby or distant genes. Common in HOX genes, lncRNAs can either regulate through cis or trans mechanisms, respectively. Cis mechanisms are transcription based when nearby genes are regulated, whereas trans mechanisms are transcript-based and regulate genes afar. HOXA11-AS regulates transcription factors and is a co-activator of the HOXA gene and other genes. Coming from HOXA homeobox, HOXA11-AS lncRNA regulates HOXA11 mRNA by blocking transcription.
HOXA11-AS is similar to other lncRNAs in that it can affect many genes at once, thus allowing both local and genome-wide control. It is also similar because of its function in regulating cell proliferation, cell cycle, migration, apoptosis, and promoting angiogenesis. Some studies have shown that overexpression causes aberrant functions of the mechanisms listed above; however, other studies have shown downregulation is the cause.
Mechanism
Not much is known about the exact mechanism of HOXA11-AS lncRNA. Studies of Drosophila however show that many intergenic regions in the HOX genes code for lncRNAs that regulate the transcription of genes. Similar to other lncRNAs, HOXA11-AS lncRNA has epigenetic control over the transcription of genes. Typically found in the nucleus of cells, HOXA11-AS lncRNA regulates the recruitment of transcription factors, and thus plays a role in chromatin remodeling. As with most lncRNAS, HOXA11-AS lncRNA is attached to the site of transcription through the Polymerase II ternary complex, which allows for allele specific action. This feature is not seen in proteins or small nuclear RNAs. LncRNAs are concentrated in the nucleus because these sequences, contained in the intron sequences, are removed from the final mRNA transcript in mRNA processing. Sequences that are not removed make up the mRNA and are capped, polyadenylated, and exported out of the nucleus.
Epigenetic proteins that are involved with lncRNAs are categorized as either: writers, readers, or erasers. These proteins either add epigenetic modifications, recognize epigenetic changes, or remove epigenetic modifications, respectively. LncRNAs are able to complementarily hybridize to DNA sequences in the genome, thus targeting sequences and localizing epigenetic changes. Oftentimes, lncRNAs are not free-floating in the nucleus and are attached to chromosomes.
Studies regarding HOX genes have found that lncRNAs are highly expressed in relation to the homeobox genes. Known antisense HOX lncRNAs, such as HOTAIR, are scaffolds where transcription factors bind, which makes them mediators of epigenetic regulation. Furthermore, this and other HOX lncRNAs are required for the normal development of the organism and are overexpressed in different forms of cancer. The overexpression of HOX lncRNA promotes cancer because it causes epigenetic regulator proteins to relocate and the chromatin of the cell to be remodeled. This remodeling can cause highly regulated functions of the cell, like proliferation, migration, and apoptosis to become unrestrained. Given the sparse research on the specific mechanism of HOXA11-AS lncRNA and what is known about the role of HOX genes, it may hold that HOXA11-AS lncRNAs act in a similar manner to other HOX lncRNAs.