HOXD. HOTAIR is highly expressed in primary breast tumors. Co-transcriptional regulation Epigenetic regulations such as DNA methylation and histone methylation can repress gene expression by inhibiting initiation of transcription. Sometimes, however, gene repression can be achieved by prematurely terminating or slowing down transcription process. AsRNAs can be involved in this level of gene regulation. For example, in bacterial or eukaryotic cells where complex RNA polymerases are present, bidirectional transcription at the same locus can lead to polymerase collision and results in the termination of transcription. Even when polymerase collision is unlikely during weak transcription, polymerase pausing can also occur which blocks elongation and leads to gene repression. One of the examples is repression of IME4 gene by its asRNA RME2. Another way of affecting transcription co-transcriptionally is by blocking splicing. One classic example in human is zinc-finger E-box binding homeobox 2 gene (ZEB2) which encodes E-cadherin, a transcriptional repressor. Efficient translation of ZEB2 mRNA requires the presence of an internal ribosome entry site (IRES) in intron of the mRNA at the 5' end. With the asRNA of ZEB2 being expressed, it can mask the splicing site and maintain the IRES in the mRNA which results in an efficient synthesis of E-cadherin. Lastly, depending on the level of asRNA expression, different isoforms of the sense transcript can be produced. Therefore, asRNA dependent regulation is not limited to on/off mechanism; rather, it presents a fine tone control system. Post-transcriptional regulation The direct post transcriptional modulation by asRNAs refers to mRNAs being targeted by asRNAs directly; thus, the translation is affected. Some characteristics of this type of asRNAs are described in the cis- and trans- acting asRNAs. This mechanism is relatively fast because both the targeting mRNA and its asRNA need to be present simultaneously in the same cell. As described in the cis-acting asRNAs, the mRNA-asRNA pairing can result in blockage of ribosome entry and RNase H dependent degradation. Overall, mRNA-targeting asRNAs can either activate or inhibit translation of the sense mRNAs with inhibitory effect being the most abundant. Therapeutic potential As a regulatory element, asRNAs bear many advantages to be considered as a drug target. First of all, asRNAs regulate gene expression at multiple levels including transcription, post-transcription and epigenetic modification. Secondly, the cis-acting asRNAs are sequence specific and exhibits high degree of complementarity with the targeting genes. Thirdly, the expression level of asRNAs is very small compared to that of