In biology, the classical view of gene expression and regulation has been focused around protein-coding genes via the central dogma of DNA → mRNA → protein. However, over the past decade, evidence from numerous next generation sequencing (NGS) experiments suggested that the evolution of developmental processes, which regulate the complexity of the organism, is mainly due to the expansion of the regulatory potential of the non-coding portions of the genome [1]. In complex organisms, the portion of the genome responsible for coding proteins constitutes approximately 1.5%, while many regulatory elements are transcribed into non-coding RNAs (ncRNAs). Indeed, the recent technological breakthrough and knowledge coming from these novel NGS techniques, established the importance of ncRNAs in the regulation of multiple major biological processes related to development, differentiation, and metabolism [2–4] and have forced us to radically reinterpret our understanding of the genome [5–7]. In contrast to the small ncRNAs, such as short interfering RNAs (siRNAs), microRNAs (miRNAs), and Piwi-interacting RNAs (piRNAs) which are highly conserved and involved in transcriptional and post-transcriptional gene expression regulation through specific base pairing with their targets, long non-coding RNAs (lncRNAs)—defined as transcribed RNA molecules greater than 200 nt in length—are poorly conserved and regulate gene expression by diverse mechanisms that are not yet fully understood [2,4,8–11].

In eukaryotes, lncRNAs have been implicated in many biological processes with different functional roles such as X chromosome inactivation [12,13], genomic imprinting [14], sub-cellular structural organization [15,16], telomere [17] and centromere organization [18,19], and nuclear trafficking [20]. Nowadays, it is well acknowledged that mammalian genomes encode numerous long non-coding RNAs [5,21–23] and that many of them are linked to fundamental biological processes and signaling network (i.e., the p53 pathway). Huarte et al. have demonstrated that numerous lncRNAs are key constituents in the p53-dependent transcriptional pathway [24]. Moreover, they observed that some of these lncRNAs are bound by p53 in their promoter regions and sufficient to drive p53-dependent reporter activity that requires the consensus p53-binding motif, suggesting that these lncRNAs are bona fide p53 transcriptional targets.

In this review, we focused the interest on those lncRNAs related to p53 regulation (induced or activating), owing to the central role of p53 in many processes. We therefore considered and discussed LincRNA-p21, PANDA, H19, MEG3 lncRNA and LincRNA-EPS.

During erythropoiesis more than 400 putative lncRNAs are differentially expressed. One of these lncRNAs, named long intergenic non-coding RNA erythroid prosurvival (LincRNA-EPS), is induced during the terminal differentiation of murine erythroid cells and has been recently investigated [28]. LincRNA-EPS is a 2531-nt lncRNA originated from a DNA portion consisting of four exons and three introns, bearing a 5′ end cap structure and a 3′ poly(A) tail. LincRNA-EPS is strongly induced when erythroid precursors begin to synthesize hemoglobin and other lineage-specific proteins. LincRNA-EPS is expressed marginally in other hematopoietic lineages, indicating erythroid specificity. It has been observed that by knocking down LincRNA-EPS, an inhibition of differentiation and the promotion of apoptosis take place. Conversely, ectopic expression of this lncRNA can prevent apoptosis in mouse erythroid cells. Although we still do not know if this LincRNA-EPS is under the direct control of p53, LincRNA-EPS can repress the expression of the proapoptotic gene Pycard, inhibiting programmed cell death [28]. On the other hand, the induction of Pycard (also known as ASC, CARD5, TMS or TMS-1) has been alternatively reported by the same authors to be either dependent on p53 (after exposure to a genotoxic stress in the intrinsic mitochondrial pathway of apoptosis through a p53-Bax network) [29] or p53-independent (under hypoxic conditions in pancreatic cancer cells) (Figure 3) [30]. However, from a preliminary bioinformatics search we found that various p53 regulatory transcription factor binding sites are present in the Pycard gene promoter (data not shown).

To study the functional link between LincRNA-EPS and Pycard and how this lncRNA can inhibit apoptosis, Hu et al. employed microarrays technology to assess the gene expression of lineage-negative (Lin-) fetal liver cells, highly enriched for erythroid progenitors [32] and ectopically expressing LincRNA-EPS. The authors found that many genes involved in apoptosis were downregulated, and the proapoptotic Pycard gene was the most downregulated. These data suggested that Pycard can be one of the targets of LincRNA-EPS and its expression during normal erythropoiesis is inversely correlated with that of the LincRNA-EPS. Moreover, the overexpression of Pycard gene is able to inhibit the proliferation of erythroid cells to promote apoptosis and interfere with their terminal differentiation and enucleation.

The nuclear localization of LincRNA-EPS suggested that the gene expression regulation might occur through nuclear events such as epigenetic modifications, transcription, or mRNA splicing, or simply by its association with chromatin modifiers which repress the transcription of Pycard and the other genes promoting cell apoptosis. Finally, further studies aimed at discovering this lncRNA and other potentially associated factors in humans and novel and more powerful computational methods and prediction algorithms will surely help to identify all the actors involved in this mechanism.

Many studies have recently identified and discussed the role of numerous lncRNAs which are involved in p53 regulation or have a role in carcinogenesis or cancer growth [40,44–48]. These lncRNAs are emerging as important regulators of gene expression by acting synergistically with other factors in many different and crucial mechanisms. The interplays between lncRNAs and p53 regulation has been discussed in this review and summarized in Figure 4.

The advent of next-generation sequencing techniques has paved the way to important discoveries also in the field of non-coding RNAs, but the exact biological role of this regulatory molecules has still to be clarified. Notwithstanding, many studies are beginning to shed light on lncRNAs and their mechanisms and more information are expected to arise in the next few years.

In this brief review, we emphasized only the role of a selection of these lncRNAs, in particular of those molecules involved in p53 pathway and in its regulation owing to the central importance of this pathway in many conditions. We are aware that many other lncRNAs may play a role in this pathway, although this role is not completely unraveled so far. Moreover, little is known about the expression level (i.e., the threshold) required to a lncRNA to function properly, or the relative abundance in various tissues. To partially answer these questions, a novel integrative approach consisting in a computational approach integrating RNA-seq data with available annotation resources has been recently reported [49]. The result is a reference catalog (Human Body Map lincRNAs) [50] of 8195 human lincRNAs with information about their expression levels in different tissues and linked to the expression of their neighboring genes.

Finally, the bioinformatics tools that will be developed in the near future will surely help researchers to fill the knowledge gaps and to face the present challenges [51]. We believe that the world of lncRNAs, as it was for the “junk” non-coding RNAs such as miRNAs, will open unexpected possibilities, not only for biological and biomedical research, but also for translational research and innovative clinical “theranostics” (therapeutics and diagnostics) applications.