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

Long noncoding RNAs (lncRNAs) have been implicated in various biological functions including regulation of gene expression, X-inactivation, imprinting, cell proliferation and differentiation. 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 a transcriptional co activator – PC4 and SF2 interacting protein (Psip1)/p52, which is involved in linking transcription to RNA processing, regulates the expression of the lncRNA Hottip. Using complementary approaches – knockdown, Cas9 mediated lncRNA deletion, analysis of lncRNA binding by Chromatin isolation by RNA purification (ChIRP) - we demonstrate that Hottip binds to the 5’ Hoxa genes located in cis, which leads to their upregulation. Moreover, the synthetic activation of Hottip is sufficient to induce the expression ofpolycomb repressed Hox genes in mouse embryonic stem cells (mESCs).