Audio: Gene Silencing by Large, Non-coding RNAs: The Regulatory Role of HOTAIR analyzed with ChIP-chip and Tiling Expression Analysis

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 large ncRNA may demarcate chromosomal domains of gene silencing from a distance. We further discuss RNA labeling optimizations, platform comparisons and the integration of ChIP-Chip and RNA expression on high-resolution DNA tiling arrays that were critical for our discovery of HOTAIR. Together, these results demonstrate the power of integrative genomics in elucidating the biological roles of large ncRNAs.