Summary: Large Noncoding RNAs (ncRNA) are becoming a distinguishing feature of the Metazoan genomes, but their functional roles are poorly understood. Here we describe a novel type of ncRNA termed HOTAIR that is 2.2. Kb RNA, has 5 spliced exons, a poly A tail and a 5’ meC cap, yet has no potential to code a sensible amino-acid sequence. HOTAIR is encoded antisense to the human HOXC cluster at the exact juncture of a 40 Kb domain of heterochromatin and a 60 Kb domain of euchromatin. However, HOTAIR doesn’t serve to regulate this boundary; Remarkably HOTAIR affects the global epigenetic state of the HOXD cluster located on a separate chromosome. HOTAIR binds the Polycomb Repressive Complex 2 (PRC2) and is required for PRC2 occupancy and histone H3 lysine-27 trimethylation of HOXD locus. Thus, transcription of ncRNA may demarcate chromosomal domains of gene silencing at a distance; these results have broad implications for gene regulation in development and disease states.
