Transcription coactivator and lncRNA duet evoke Hox genes

Mammalian genomes are pervasively transcribed [1, 2] to produce thousands of long noncoding RNAs (lncRNAs) [3–5], transcripts that are more than 200 nucleotides in length that do not code for proteins. Although only a handful of functional lncRNAs have been well characterized to date, recent work suggests that some lncRNAs have crucial roles in the control of gene expression during both normal development and disease, through multiple mechanisms [6, 7]. As new lncRNAs are being discovered at a rapid pace, their molecular mechanisms are continuing to be enriched and diversified. For example, a few lncRNAs have been shown to affect expression of nearby genes through recruitment of protein regulatory complexes [8–10], while it is suggested that others function akin to enhancers and local regulators in cis [11, 12]. In fact, such local gene-regulatory mechanisms have been invoked to explain the observation that lncRNA expression is often correlated with the expression of nearby genes—the so-called “guilt by association” [13]. The cis-acting mechanisms of lncRNAs are largely unknown. Whether loci encoding lncRNAs function via their lncRNA transcripts or DNA elements is often unclear. An important question in the field centers around distinguishing between at least 2 possible mechanisms—either the function of many of the lncRNAs that appear to regulate genes in cis depends on the RNAs themselves or their effect is mediated by enhancer-like activity of underlying DNA elements in the lncRNA locus, the act of transcription, and/or splicing of lncRNAs [14, 15]. Furthermore, the molecular components regulating the expression of lncRNAs remain mostly unexplored. An understanding of the possible commonalities of the disparate underlying mechanisms may facilitate instructive and predictive models of lncRNA function. Pradeepa et al. [16] set out to elucidate 1 mechanism of lncRNA regulation and function using the HoxA locus as their model. The Bickmore group had previously shown that positive cofactor 4 (PC4) and splicing factor 2 (SF2) interacting protein (Psip1), also known as lens epithelium-derived growth factor (LEDGF), played an important role in the regulation of Hox genes [17] and had more recently demonstrated the role of the p75 isoform of Psip1 (Psip1/ p75) in recruiting the Trithorax/mixed lineage leukemia (MLL) complex to expressed Hox genes [18]. Interestingly, loss of Psip1 led not only to reduced binding of the MLL complex and loss of histone 3 lysine 4 trimethylation (H3K4me3) at the distal HoxA genes, it also resulted in complete loss of expression of the lncRNA HoxA transcript at the distal tip (Hottip), transcribed in an antisense direction away from the distal end of the 5 HoxA cluster [10]. This suggested that Psip1 might function as a transcriptional regulator of Hottip expression. Following up on this possible connection, the authors showed that knockdown of Psip1/p52, the p52 isoform of Psip1, or Hottip, led to down-regulation of multiple 5 HoxA genes; knockdown of