A myelopoiesis-associated regulatory intergenic noncoding RNA transcript within the human HOXA cluster

Abstract

We have identified an intergenic transcriptional activity that is located between the human HOXA1 and HOXA2 genes, shows myeloid-specific expression, and is upregulated during granulocytic differentiation. The novel gene, termed HOTAIRM1 (HOX antisense intergenic RNA myeloid 1), is transcribed antisense to the HOXA genes and originates from the same CpG island that embeds the start site of IntroductionHuman HOX gene clusters are known for the prevalence of intergenic transcription between coding genic members. 1 Similar activity has also been observed in other developmentally important or tissue-specific gene loci, such as those containing the human beta globin genes, cardiac myosin heavy chain genes, and the interleukin-4 (IL-4)/IL-13 gene cluster. [2][3][4] Extensive HOX gene cluster intergenic transcripts have been described largely as noncoding RNAs (ncRNAs), including both short microRNA (miRNA) species and long ncRNAs that are antisense to their canonical HOX neighbors. Well-defined HOX region ncRNAs include the mir-10 and mir-196 paralogs, bithoraxoid ncRNAs of the Drosophila bithorax complex, and human HOX antisense intergenic RNA (HOTAIR). [5][6][7] Intergenic regions have been proposed as locations for novel radiational and reorganizing changes that have occurred in the evolution of HOX gene clusters, which are relatively constrained in structure in the higher vertebrates. 5,8 Several recent studies have focused on expression of intergenic ncRNAs in the human HOX regions, especially the HOXA cluster, in tumor cell lines, tissues, and fibroblasts from different anatomic origins. All reported unusually active transcription within the intergenic regions, occurring in patterns coordinated with their HOX neighbors. 7,9,10 Intergenic ncRNAs in the HOXA gene cluster were usually associated with CpG islands and their expression accompanied changes in either polycomb group repressive complex binding or methylation of histones, suggesting a pattern of cis modulation of the intergenic transcripts before the activation of adjacent HOX genes. However, the HOTAIR transcript, located between HOXC11 and HOXC12, was found to function in trans to repress a distal group of homologous HOXD genes by demarcating an extended silenced domain through interaction with the polycomb group complex PRC2 histone methyltransferase 7,10,11 De novo genomic transcription mapping has revealed that intergenic ncRNA is possibly the most abundant form of transcriptional output from the genomes of humans and other higher eukaryotic organisms. 12,13 Within the human genome, the majority of intergenic ncRNA are not highly conserved at the sequence level, with long ncRNAs generally less conserved than short miRNAs. Nevertheless, their expression patterns may be conserved among tissues or along developmental axes. 14,15 More importantly, ncRNA function in gene regulation has emerged as an important mechanism in the control of many biologic processes in development and carcinogenesis. 16 In the present study, we have identified intergenic transc...

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