Privileged Communication Writer Meets Eraser in HOTAIR

Polycomb-group (PcG) proteins and associated histone modifications play pivotal roles in development, stem cell self-renewal and cancer. These proteins function in different transcriptional repressor complexes that epigenetically modify chromatin and participate in the establishment and maintenance of cell fates [1]. Although many proteins have been reported to associate with PcG protein complexes for transcriptional repression, the recent discovery of a link between long intergenic non-coding RNAs (lincRNAs) and PcG proteins added another regulatory layer for the diverse functions of PcG proteins [2, 3]. In a report published in a recent issue of Science [4], Tsai et al. further demonstrated that a lincRNA termed HOX Antisense Intergenic RNA (HOTAIR) not only functions as a molecular scaffold to link Polycomb repressive complexes 2 (PRC2) and lysine specific demethylase 1/REST corepressor 1/RE1-silencing transcription factor (LSD1/CoREST/REST) protein complexes, but also coordinates the chromatin targeting of these proteins and in turn couples histone H3K27 methylation and H3K4 demethylation for epigenetic gene silencing [4]. PcG proteins were initially identified in Drosophila as essential regulators for correct spatial expression of homeotic (HOX) genes during development. The Polycomb family comprises a structurally diverse set of proteins that reside in two main complexes, named PRC1 and PRC2 [5]. The core of the PRC2, which comprises SUZ12, EED, RBAP48/46 and EZH2, methylates histone at H3K27 (H3K27me2/3) and at H1K26 (H1K26me), whereas the core of the PRC1, which contains CBX, BMI1, PH, and RING, catalyzes the mono-ubiquitylation of histone H2AK119 (H2AK119ub1). The interplay model for different PRCs and their catalyzed histone modifications has been proposed. PRC2 is first recruited to specific genomic locations to catalyze H3K27me3. Methylated-H3K27 then serves as a recognition site to further recruit PRC1, which in turn introduces H2AK119ub1 marks and impedes RNA polymerase II elongation [1,5]. Furthermore, PcG proteins also associate with other chromatin-modifying enzymes for transcriptional repression. For example, EED binds to HDACs, while EZH2 directly interacts with DNA methyltransferases, suggesting a biochemical and functional link among different repressive epigenetic machineries. In addition, JmjC domain-containing H3K4 histone demethylases RBP2 and SMCY have also been linked to PcG-mediated transcriptional repression by removing the H3K4me2/3 activation marks [1]. Given that neither PRC1 nor PRC2 core complex has DNA-binding motifs, one of the essential questions for the PcG-mediated repression mechanism is how PcG proteins are recruited and dissociated from target genes during development and differentiation. In Drosophila, transcription factors (e.g. PHO and PHO-like proteins) can recruit PcG proteins to DNA sequences termed Polycomb response elements (PREs) [1]. However, PcG targeting sequences in mammals are not well understood. In mice, a DNA fragment named PRE-kr can recruit both PRC1 and PRC2 to repress MafB gene expression in a PcG-dependent manner, and thus has been proposed as the first mouse PRE [6]. More recently, a 1.8-kb region between the HOXD11 and HOXD12 loci (D11.12) has been characterized as the first potential PRE in human ES cells. This D11.12 sequence possesses several typical PRE characteristics and contains a cluster-binding sites for YY1 (mammalian ortholog of PHO), which is a known human DNA-binding protein to recruit PcG proteins for transcriptional repression. However, mutation of YY1-binding sites only impairs PRC1 recruitment but not PRC2 binding or H3K27me3 states, indicating that other factors might be also involved in the PcG recruitment in this region [7]. The HOX genes encode a group of key transcription factors important for development, which are regulated by PcG and trithorax-group (trxG) proteins through various epigenetic mechanisms [8]. Recent studies uncovered a large group of lincRNAs in the Hox loci that are differentially expressed along developmental axes and possess unique sequence motif [3]. As a lincRNA transcribed from the HOXC cluster in an antisense manner, HOTAIR is required to maintain a transcriptionally silent chromosomal domain in trans across the 40 kb HOXD locus. HOTAIR also physically associates with PRC2 and knocking-down Acta Biochim Biophys Sin 2011, 43: 1–3 | a The Author 2010. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. DOI: 10.1093/abbs/gmq110. Advance Access Publication 6 December 2010