Abstract
Long non-coding RNAs regulate various biological processes such as dosage compensation, imprinting, and chromatin organization. HOTAIR, a paradigm of this new class of RNAs, is localized within the human HOXC gene cluster and was shown, in human cells, to regulate HOXD genes in trans via the recruitment of Polycomb Repressive Complex 2 (PRC2), followed by the trimethylation of lysine 27 of histone H3. We looked for the presence of Hotair in mice to assess whether this in trans mechanism was conserved, in particular at the developmental stages, when Hoxd genes must be tightly regulated. We show that the cognate mouse Hotair is poorly conserved in sequence; and its absence, along with the deletion of the HoxC cluster, has surprisingly little effect in vivo, neither on the expression pattern or transcription efficiency, nor on the amount of K27me3 coverage of different Hoxd target genes. We conclude that Hotair may have rapidly evolved within mammals and acquired a functional importance in humans that is not easily revealed in mice. Alternatively, redundant or compensatory mechanisms may mask its function when studied under physiological conditions.
Highlights
Genomes contain a large number of RNAs, which do not encode any protein [1,2,3,4,5]
HOTAIR, a human lincRNA localized within the HOXC cluster was shown to help silence HOXD cluster genes in trans, through the recruitment of the Polycomb Repressive Complex (PRC2)
We investigated the role of the murine mHotair lincRNA and report that both its structure and function are quite different from that described in human cells
Summary
Genomes contain a large number of RNAs, which do not encode any protein [1,2,3,4,5] While some of these non-coding RNAs such as XIST, TSIX and AIR associate with epigenetic modifying complexes [6,7,8,9,10,11], the functions of others remain poorly understood. Recent studies have shown that distinct lincRNAs are involved in diverse biological processes such as dosage compensation, imprinting or cancer metastasis [10,18,19,20] They may function at the interface between DNA and its epigenetic regulation by targeting remodeling complexes to their target sites [21]. Knock-down of HOTAIR in human fibroblasts induced gain of expression of different members of the HOX family, associated with a loss of K27me decorating part of the HOXD locus in these cells [10]
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