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Long noncoding RNAs (lncRNAs) have been implicated in various biological functions including the regulation of gene expression, however, the functionality of lncRNAs is not clearly understood and conflicting conclusions have often been reached when comparing different methods to investigate them. Moreover, little is known about the upstream regulation of lncRNAs. Here we show that the short isoform (p52) of a transcriptional co-activator—PC4 and SF2 interacting protein (Psip1), which is known to be involved in linking transcription to RNA processing, specifically regulates the expression of the lncRNA  Hottip– located at the 5’ end of the Hoxa locus. Using both knockdown and knockout approaches we show that  Hottip  expression is required for activation of the 5’ Hoxa genes ( Hoxa13  and  Hoxa10/11 ) and for retaining Mll1 at the 5’ end of Hoxa. Moreover, we demonstrate that artificially inducing  Hottip  expression is sufficient to activate the 5’ Hoxa genes and that  Hottip  RNA binds to the 5’ end of Hoxa. By engineering premature transcription termination, we show that it is the  Hottip  lncRNA molecule itself, not just  Hottip  transcription that is required to maintains active expression of posterior Hox genes. Our data show a direct role for a lncRNA molecule in regulating the expression of developmentally-regulated mRNA genes  in cis .

Psip1/p52 regulates posterior Hoxa genes through activation of lncRNA Hottip