Long non-coding RNA-regulated pathways in pancreatic β cells: Their role in diabetes

Abstract

Long non-coding RNAs (lncRNAs) are transcripts of more than 200 nucleotides that have not coding potential, but act as gene expression regulators through several molecular mechanisms. Several studies have identified tons of lncRNAs that are expressed in pancreatic β cells and many of them have been shown to have β cell-specific expression, suggesting a potential role in the regulation of basal β cell functions. Indeed, accumulating evidence based on numerous studies, has highlighted the implication of lncRNAs in the regulation of pancreatic β cell differentiation and proliferation, insulin synthesis and secretion, and apoptosis.

In addition, several lncRNAs have shown to be implicated in pancreatic β cell dysfunction linked to different types of diabetes, including type 1 and type 2 diabetes, and monogenic forms of the disease. Pathogenic conditions linked to diabetes (inflammation or lipoglucotoxicity, for example) dysregulate the expression of several lncRNAs, suggesting that changes in lncRNA may alter potentially important pathways for β cell function, and eventually leading to β cell dysfunction and diabetes development. In this sense, functional characterization of some lncRNAs has demonstrated that these non-coding molecules participate in the regulation of several crucial pathways at the pancreatic β cell level, and dysregulation of these pathways leads to pathogenic phenotypes.

In this review, we provide an overview of the action mechanisms of functionally characterized lncRNAs in healthy β cells and describe the contribution of some diabetes-associated lncRNAs to pancreatic β cell failure.

Introduction

According to the central dogma of molecular biology, genetic information flows from DNA to RNA and finally, to protein. However, during the last years, this dogma has turned upside down due to the discovery of tons of genes that transcribe into RNA molecules that do not produce any protein. These non-coding RNA molecules were vastly called “junk DNA” and were supposed not to carry out any relevant biological function, however recent advantages in our understanding of non-coding RNA biology has revealed that these molecules are crucial regulators of several key biological processes, including random X chromosome inactivation, imprinting, cell cycle, organogenesis, differentiation and pluripotency (Guttman et al., 2011; Hung et al., 2011; Klattenhoff et al., 2013; Penny et al., 1996).

Advances in high-throughput sequencing techniques and in the annotation of the human genome have revealed that only about 2% of the genome has coding potential and hence, that most of the genome is constituted by non-coding genes (Dunham et al., 2012) (Fig. 1). Many of these non-coding genes transcribe for long non-coding RNAs (lncRNAs), which are defined as RNA molecules longer than 200 bp without potential to encode any protein. In contrast to protein-coding transcripts, lncRNAs are usually expressed in lower abundance and their expression is generally tissue- or cell-specific (Mercer et al., 2009).

LncRNAs are crucial regulators of gene transcription through different molecular mechanisms. Initially, these transcripts were shown to function locally, near their sites of synthesis, by regulating the expression of neighboring genes. More recently, it has been demonstrated that lncRNAs are able to interact with chromatin at several thousand different locations across multiple chromosomes to modulate large-scale gene expression (Vance and Ponting, 2014). Although the mode of action of most lncRNAs remains to be clarified, several studies have linked lncRNAs with the control of several processes including protein synthesis, RNA maturation, splicing and stability, transport and transcriptional gene silencing/activation through regulation of the chromatin structure (Bhat et al., 2016; Böhmdorfer and Wierzbicki, 2015; Romero-Barrios et al., 2018; Wang and Chang, 2011) (Fig. 2).

As lncRNAs are implicated in several regulatory processes, they emerge as potential mediators in the development of several human pathologies (Delás and Hannon, 2017; DiStefano, 2018). Indeed, many lncRNAs are enriched for disease-associated single nucleotide polymorphisms (SNPs), suggesting that these genetic variants might alter the function of lncRNAs and have an impact in relevant pathways for disease pathogenesis which include cancer, immune-related disorders and cardiometabolic traits (Castellanos-Rubio and Ghosh, 2019; Giral et al., 2018; Kumar et al., 2013; Mirza et al., 2014).

Taking into account that interactions of lncRNAs with other molecules (DNA, RNA or proteins) are governed by their structure, rather than by their sequences, polymorphisms altering the secondary structure of lncRNAs may have an impact in their capacity to interact with other molecules, leading to altered biological pathways. Disease-associated SNPs may also impact in lncRNAs function by disturbing their expression levels or by modifying the alternative splicing of the transcript, for example (Kumar et al., 2013). Although many SNPs located in lncRNAs have been associated with pathogenic conditions, the impact of these polymorphisms in the function of lncRNAs and their contribution to disease pathogenesis remains to be clarified.

In this chapter, we focus on lncRNAs expressed in pancreatic islets and β cells to describe their function in basal biological processes and their implication in pathogenic conditions linked to pancreatic β cell dysfunction, such as type 1 and type 2 diabetes mellitus. We provide an overview of the action mechanisms of functionally characterized lncRNAs in healthy β cells and describe the contribution of some diabetes-associated lncRNAs to pancreatic β cell failure.