Date Published: November 20, 2018
Publisher: John Wiley and Sons Inc.
Author(s): António Sousa‐Franco, Kenny Rebelo, Simão Teixeira da Rocha, Bruno Bernardes de Jesus.
One of the most outstanding observations from next‐generation sequencing approaches was that only 1.5% of our genes code for proteins. The biggest part is transcribed but give rise to different families of RNAs without coding potential. The functional relevance of these abundant transcripts remains far from elucidated. Among them are the long non‐coding RNAs (lncRNAs), a relatively large and heterogeneous group of RNAs shown to be highly tissue‐specific, indicating a prominent role in processes controlling cellular identity. In particular, lncRNAs have been linked to both stemness properties and detrimental pathways regulating the aging process, being novel players in the intricate network guiding tissue homeostasis. Here, we summarize the up‐to‐date information on the role of lncRNAs that affect stemness and hence impact upon aging, highlighting the likelihood that lncRNAs may represent an unexploited reservoir of potential therapeutic targets for reprogramming applications and aging‐related diseases.
The rapid progression of next‐generation sequencing (NGS) has produced an enormous amount of descriptive data on the expression profiles of several coding and non‐coding transcripts (Carninci et al., 2005). Different consortiums, namely the ENCODE project, mapped expression data in a variety of cell types and conditions including stem, progenitor, and somatic cells (Bernstein et al., 2012). One of the first surprises came with the observation that the amount of coding genes was lower than initially expected and was paralleled with an exponential identification of RNA species lacking coding potential. Additionally, high interspecies variance at the non‐coding level was encountered, suggesting a role for non‐coding transcription in determining species identity (Mattick & Makunin, 2006). Furthermore, it has been demonstrated that non‐coding RNAs present much higher tissue specificity than protein‐coding genes, highlighting their importance for tissue‐specific function/identity (Cabili et al., 2011). Non‐coding RNAs play important regulatory roles in modulating transcriptionally and post‐transcriptionally the coding transcriptome (Angrand, Vennin, Bourhis, & Adriaenssens, 2015; Mattick & Makunin, 2006), which starts to be unveiled in pathological conditions such as cancer. However, how the non‐coding transcriptome diverges from cellular stemness to tissue commitment and aging, and they impact on those processes, remains elusive.
Several alternatives in vitro methodologies have been optimized for the reprogramming and/or expansion of embryonic‐like stem cells from adult tissue. In particular, Yamanaka and colleagues found that expression of four transcription factors, namely Sox2, Klf4, Oct4, and c‐Myc, in adult human and mice skin fibroblasts converts them to a “stem‐like” condition named induced pluripotent stem cells (iPSCs; Takahashi & Yamanaka, 2006; Yamanaka, 2009). The possibility to replace the original retroviral and lentiviral vectors through the use of nonintegrative strategies was tested and is being used since then (Sun, Longaker, & Wu, 2010), and this included non‐coding RNA players. Indeed, soon after the release of the initial iPSC reprogramming protocol, a report revealed that introducing miRNA mimics of embryonic stem cells (ESCs) specific miRNAs enhanced mouse iPSC derivation and replaced the function of c‐Myc during reprogramming (Judson, Babiarz, Venere, & Blelloch, 2009). Scrutinizing the differential distribution of the coding and non‐coding transcriptome between stem and differentiated cells may unveil novel targetable reprogramming barriers. Due to the gain of regenerative potential during cellular reprogramming, it has been thought as useful to the aging field (Ocampo, Reddy, & Belmonte, 2016; Soria‐Valles & Lopez‐Otin, 2016). Induced pluripotent cells obtained during cellular reprogramming of aged tissue reset their stress‐ and senescence‐associated epigenetic marks (Lapasset et al., 2011; Liu et al., 2011; Zhang et al., 2011). Erasure of the aging marks is a crucial step during cellular and tissue regeneration strategies.
As mentioned before, lncRNAs are emerging as potential targets for anti‐aging therapies. Their non‐coding nature and particularities (such as the conformational complexity, cellular localization, or interactions) need to be taken into consideration in the design of strategies for efficient lncRNA modulation.