The Mission of Long Non-Coding RNAs in Human Adult Renal Stem/Progenitor Cells and Renal Diseases

Abstract

Long non-coding RNAs (lncRNAs) are a large, heterogeneous class of transcripts and key regulators of gene expression at both the transcriptional and post-transcriptional levels in different cellular contexts and biological processes. Understanding the potential mechanisms of action of lncRNAs and their role in disease onset and development may open up new possibilities for therapeutic approaches in the future. LncRNAs also play an important role in renal pathogenesis. However, little is known about lncRNAs that are expressed in the healthy kidney and that are involved in renal cell homeostasis and development, and even less is known about lncRNAs involved in human adult renal stem/progenitor cells (ARPC) homeostasis. Here we give a thorough overview of the biogenesis, degradation, and functions of lncRNAs and highlight our current understanding of their functional roles in kidney diseases. We also discuss how lncRNAs regulate stem cell biology, focusing finally on their role in human adult renal stem/progenitor cells, in which the lncRNA HOTAIR prevents them from becoming senescent and supports these cells to secrete high quantities of α-Klotho, an anti-aging protein capable of influencing the surrounding tissues and therefore modulating the renal aging.

Keywords: adult renal progenitor cells; lncRNA HOTAIR; long non-coding RNAs; renal disease; stem cell biology.

Figure 1

Classification of lncRNA functions. LncRNAs act as regulators of gene expression: (a,h) they can influence chromatin architecture by interacting with different protein components of the remodeling complex and modifying chromatin organizational patterns. (b) They activate the transcription of certain genes by driving transcription factors to their promoters and by targeting transcriptional modulators such as RNA polymerase (RNAP) II; (c) however, they are also capable of suppressing transcription by sequestering transcription factors and keeping them away from their promoters. LncRNAs also control various aspects of post-transcriptional mRNA processing, including: (d) they perform scaffolding roles by providing docking sites for proteins that function together in the same biological pathway; (e) through binding to protein interactors, including classical RNA-binding proteins (RBPs), they are able to modulate mRNA functioning by also subjecting them to degradative pathways; (f) they act like “sponges” by base pairing with their complementary miRNAs and reducing their effects; (g) they alter their splicing patterns.

Figure 2

Regulatory mechanisms of lncRNAs in stem cells. (a) Several lncRNAs interact in the canonical Wnt signaling cascade and influence the expression of genes by inducing or inhibiting cell differentiation. (b) The p53-regulated, long non-coding PRESS1 physically interacts with SIRT6 and inhibits its attachment to chromatin, controlling a gene network that promotes the pluripotency of hESCs (human embryonic stem cells) by maintaining high levels of histone H3K56 and H3K9 acetylation in the promoters of pluripotency genes such as OCT4 and NANOG. (c) The lncRNA Gm15055, whose expression is influenced by OCT4, represses HoxA gene expression by recruiting PRC2 to the cluster and maintaining the H3K27me3 modification on HoxA promoters in mESCs (mouse embryonic stem cells); (d) The nuclear lncRNA HOTAIRm1 also regulates HoxA expression, leading to trimethylation of histone H3K27 and epigenetic silencing of the gene; furthermore, it promotes the acetylation of H3K27 in the enhancer site of the NANOG gene by upregulating its expression and inhibiting HoxA, which creates a reciprocal regulatory loop that increases the stemness effect. (e) Some lncRNAs enhance epigenetic reprogramming by coordinating intrachromosomal looping and by recruiting the TET2 demethylase, promoting DNA demethylation at the OCT4 and SOX2 promoters.

Figure 3

HOTAIR regulates ARPC stemness properties. HOTAIR regulates the proliferation and self-renewal capacity of ARPCs, limits their apoptosis, and regulates CD133 expression, an inverse marker of senescence and functional marker of stemness in ARPCs. HOTAIR also regulates the secretion of α-Klotho, which in turn can influence the surrounding tissues and therefore modulate tissue aging, playing an important role in preventing cells from becoming senescent in the short term. These mechanisms are regulated through p15 epigenetic silencing by HOTAIR. This lncRNA acts as a molecular scaffold to link the PRC2 and LSD1 protein complexes and coordinates the chromatin targeting of these proteins. The complex leads to histone H3K27 trimethylation and H3K4 demethylation in the p15 gene promoter. Trimethylation of H3K27 leads to the silencing of cyclin p15 and helps keep the ARPC cell cycle active, sustaining self-renewal and proliferation. From: Angela Picerno, Francesca Giannuzzi, Claudia Curci, Giuseppe De Palma, Mariagiovanna Di Chiano, Simona Simone, Rossana Franzin, Anna Gallone, Vito Francesco Di Lorenzo, Alessandra Stasi, Giovanni Battista Pertosa, Carlo Sabbà, Loreto Gesualdo, Fabio Sallustio, The Long Non-coding RNA HOTAIR Controls the Selfrenewal, Cell Senescence, and Secretion of Anti-aging Protein Klotho in Human Adult Renal Progenitor Cells, Stem Cells, 2022, Page 11, with permission of Oxford University Press.