The long noncoding RNA Gm15055 represses Hoxa gene expression by recruiting PRC2 to the gene cluster

The Hox genes encode transcription factors that determine embryonic pattern formation. In embryonic stem cells, the Hox genes are silenced by PRC2. Recent studies have reported a role for long noncoding RNAs in PRC2 recruitment in vertebrates. However, little is known about how PRC2 is recruited to the Hox genes in ESCs. Here, we used stable knockdown and knockout strategies to characterize the function of the long noncoding RNA Gm15055 in the regulation of Hoxa genes in mouse ESCs. We found that Gm15055 is highly expressed in mESCs and its expression is maintained by OCT4. Gm15055 represses Hoxa gene expression by recruiting PRC2 to the cluster and maintaining the H3K27me3 modification on Hoxa promoters. A chromosome conformation capture assay revealed the close physical association of the Gm15055 locus to multiple sites at the Hoxa gene cluster in mESCs, which may facilitate the in cis targeting of Gm15055 RNA to the Hoxa genes. Furthermore, an OCT4-responsive positive cis-regulatory element is found in the Gm15055 gene locus, which potentially regulates both Gm15055 itself and the Hoxa gene activation. This study suggests how PRC2 is recruited to the Hoxa locus in mESCs, and implies an elaborate mechanism for Hoxa gene regulation in mESCs.