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

Abstract

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.

lncRNAs: function and mechanism in cartilage development, degeneration, and regeneration

“…LncRNA used as an approach to treat cartilage-related disease is in infancy. As reported by Gogtay, nucleic acid could act as a therapeutic agent [95]. Owing to many lncRNAs involved in the pathological process of cartilage-related diseases, lncRNAtargeting therapy may be a new hope for treatment.…”

“…Exogenous overexpression of PCGEM1 could induce the proliferation of synoviocyte [28]. Another lncRNA HOTTIP is located within the HoxA cluster and worked by interacting with histone modification complexes [95]. The study by Kim et al [26] illustrated that the expression of HOTTIP was upregulated in OA chondrocytes with modulating HoxA13 gene level.…”

Regulatory landscape of the Hox transcriptome

“…Within the vertebrate Hox clusters, Hottip is a good example of a two-tiered mode of action, as both the lncRNA gene locus and the noncoding RNA transcript play a role in chromatin remodelling and recruitment of histone modifiers to facilitate the transcription of neighbouring Hox genes. Located upstream of Hoxa13 in both mice (Fig 2;Sasaki et al, 2007;Wang et al, 2011) and humans (Rinn et al, 2007;Wang et al, 2011), Hottip recruits the MLL complex via binding to Wdr5, resulting in the deposition of H3K4me4 marks on 5' HoxA genes and thus keeping them transcriptionally active (Wang et al, 2011;Pradeepa et al, 2017). Additionally, chromatin conformation capture technology identified physical interactions between the Hottip locus and 5' HoxA genes by chromatin looping (Wang et al, 2011).…”

Integrated Analysis of lncRNA, miRNA and mRNA Reveals Novel Insights into the Fertility Regulation of Large White Sows

“…On the other hand, miRNAs are an abundant class of short (18-24 nucleotides) and highly conserved sequences of endogenous RNAs, which have been extensively studied in many species [14]. Previous studies have prospectively con rmed that ncRNAs (miRNAs and lncRNAs) were considered as crucial players in both humans and animals, and affect various biological functions [12,[15][16][17]. Moreover, there is substantial evidence supporting that lncRNAs, acting as competing endogenous RNAs (ceRNAs), contribute to the regulation of cardiac brosis [18], muscle differentiation [19] and tumorigenesis [20,21].…”