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Roles of Noncoding RNAs in Islet Biology

Claudiane Guay, Cécile Jacovetti, Mustafa Bilal Bayazit, Flora Brozzi, Adriana Rodriguez‐Trejo, Kejing Wu, Romano Regazzi

10.1002/cphy.c190032

Source: Volume 10, Issue 3, July 2020

Published online: July 2020

Full Article on Wiley Online Library



Abstract

The discovery that most mammalian genome sequences are transcribed to ribonucleic acids (RNA) has revolutionized our understanding of the mechanisms governing key cellular processes and of the causes of human diseases, including diabetes mellitus. Pancreatic islet cells were found to contain thousands of noncoding RNAs (ncRNAs), including micro‐RNAs (miRNAs), PIWI‐associated RNAs, small nucleolar RNAs, tRNA‐derived fragments, long non‐coding RNAs, and circular RNAs. While the involvement of miRNAs in islet function and in the etiology of diabetes is now well documented, there is emerging evidence indicating that other classes of ncRNAs are also participating in different aspects of islet physiology. The aim of this article will be to provide a comprehensive and updated view of the studies carried out in human samples and rodent models over the past 15 years on the role of ncRNAs in the control of α‐ and β‐cell development and function and to highlight the recent discoveries in the field. We not only describe the role of ncRNAs in the control of insulin and glucagon secretion but also address the contribution of these regulatory molecules in the proliferation and survival of islet cells under physiological and pathological conditions. It is now well established that most cells release part of their ncRNAs inside small extracellular vesicles, allowing the delivery of genetic material to neighboring or distantly located target cells. The role of these secreted RNAs in cell‐to‐cell communication between β‐cells and other metabolic tissues as well as their potential use as diabetes biomarkers will be discussed. © 2020 American Physiological Society. Compr Physiol 10:893‐932, 2020.

Figure 1. Figure 1. Regulation of β‐cell mass over lifetime. The functional β‐cell mass is regulated by different processes over the course of a lifetime. During embryonic development and the neonatal period, expansion of the β‐cells is critical for the acquisition and the maintenance of a fully functional β‐cell mass. Adverse conditions limiting β‐mass expansion during these critical periods predispose individuals to diabetes later in life. Pancreatic β‐cells can be the target of an autoimmune attack. Immune cells infiltrate the islets and selectively kill the β‐cells, leading to a near complete loss of insulin‐secreting cells and the appearance of type 1 diabetes. Throughout life, several mechanisms favor the expansion of the functional β‐cell mass during pregnancy or in obese individuals to compensate for insulin resistance of peripheral tissues. Type 2 diabetes develops if the functional β‐cell mass fails to adapt to cover the increased insulin needs. Lastly, aging and β‐cell senescence can reduce the capacity to compensate for insulin resistance.
Figure 2. Figure 2. Relative amounts of RNA transcripts in human and mouse cells. Pie chart representing the proportion of different RNA classes compared to the total number of annotated genes in (A) human (60,603 genes) or (B) mouse (55,487 genes). Data obtained from Gencode 31. Abbreviations: lncRNAs, long‐noncoding ribonucleic acids; miRNAs, micro‐ribonucleic acids; snoRNAs, small nucleolar ribonucleic acids; snRNAs, small nuclear ribonucleic acids; ncRNAs, noncoding ribonucleic acids.
Figure 3. Figure 3. Classification of RNAs. RNA molecules can be divided into two categories, depending on their ability to code (coding RNA) or not (noncoding RNA) for proteins. Noncoding RNA transcripts are classified based on their function (rRNA, ribosomal ribonucleic acid; tRNA, transfer ribonucleic acid) or on their length (shorter or longer than 200 nucleotides). The short RNA families include snoRNAs (small nucleolar ribonucleic acids), snRNAs (small nuclear ribonucleic acids), siRNAs (small interfering ribonucleic acids), miRNAs (micro‐ribonucleic acids), and piRNAs (PIWI‐interacting ribonucleic acids). The long‐noncoding ribonucleic acid (lncRNA) family is further subdivided based on the shape of the RNA molecules: linear lncRNA or circular ribonucleic acid (circRNA). Of note, tRNA molecules can be cleaved to generate fragments (tRF) that share some properties with other short ncRNAs.
Figure 4. Figure 4. Generation and classification of tRFs. Endonucleic cleavage of mature tRNAs generates a diverse range of tRFs. Various endonucleases including Dicer generate short tRFs (12–20 nucleotides) at either arms of the tRNAs. Alternatively, angiogenin cleaves tRNAs at the anticodon loop, generating tRNA halves (32–50 nucleotides, also known as tiRNAs). A double cleavage along the length of tRNAs can generate internal tRNA fragments (16 nucleotides or longer, also known as i‐tRFs).
Figure 5. Figure 5. Classification of lncRNAs based on their genomic proximity to protein‐coding genes. (A) Long intergenic noncoding ribonucleic acids (lincRNAs) are located in intergenic regions. They are situated at more than 1 kb distance from the nearest protein‐coding genes. (B) The other classes of long noncoding ribonucleic acids (lncRNAs) are located in the vicinity of protein‐coding genes and are named based on how their exons are positioned on the genome with respect to the exons of the mRNA and on the direction of transcription: overlapping, intronic, cis‐antisense, or bidirectional.
Figure 6. Figure 6. Examples of mode of action of lncRNAs in β‐cells. (A) The lncRNA PLUTO acts on 3D chromatin organization to favor the transcription of PDX1 by bringing in close proximity the PDX1 promoter with its enhancer cluster. (B) The lncRNA Meg3 inhibits EZH2‐mediated methylation of Rad21, Smc3, and Sin3α promoters, triggering the expression of these transcription factors and, therefore, resulting in the inhibition of MafA expression. (C) The lncRNA H19 sequesters let‐7 members to prevent the repression of target genes of these miRNAs, leading to activation of the PI3K/AKT pathway. Abbreviations: lncRNA, long noncoding ribonucleic acid; miRNA, micro‐ribonucleic acid; PI3K, phosphatidylinositol 3‐kinase.
Figure 7. Figure 7. Formation of circular RNAs in eukaryotic cells. Eukaryotic circRNAs can be generated from introns (gray) and/or exons (colored) of pre‐mRNAs. Circular intronic RNAs (left) arise from introns circularized at the 5′ and branchpoint (bp) nucleotides by a 2′ to 5′ junction during linear splicing. These branched circular introns have a linear 3′ tail and are known as lariats. Intron lariats can be debranched and rapidly degraded or escape debranching, lose their tail, and turn into stable circular intronic RNAs. Instead, circular exonic and exonic‐intronic RNAs (right) can contain one or more exons and/or introns and are produced by backsplicing of an upstream 3′ splice site and a downstream 5′ splice site circularized by a 3′ to 5′ junction.
Figure 8. Figure 8. Exosome cross talk in the context of type 1 and type 2 diabetes. (A) In the context of T1D, islet mesenchymal stem cells (i‐MSC) and β‐cells secrete exosomes that activate T‐ and B‐cells. Pancreatic islet cells produce exosomes that can horizontally transfer genetic material to adjacent islet cells and endothelial cells. Infiltrated T‐cells transfer specific miRNAs via exosomes to β‐cells. (B) In the context of T2D, muscle and hepatic exosomes deliver miRNAs to pancreatic islet cells. Exosomes secreted from adipose tissue macrophages (ATMs) transfer miRNAs to insulin target tissues. Adipose tissue release exosomes containing miRNAs to liver and skeletal muscle. (A,B) Pancreatic islet exosomes and ncRNAs that are released in the blood stream represent potential biomarkers for T1D and T2D.


Figure 1. Regulation of β‐cell mass over lifetime. The functional β‐cell mass is regulated by different processes over the course of a lifetime. During embryonic development and the neonatal period, expansion of the β‐cells is critical for the acquisition and the maintenance of a fully functional β‐cell mass. Adverse conditions limiting β‐mass expansion during these critical periods predispose individuals to diabetes later in life. Pancreatic β‐cells can be the target of an autoimmune attack. Immune cells infiltrate the islets and selectively kill the β‐cells, leading to a near complete loss of insulin‐secreting cells and the appearance of type 1 diabetes. Throughout life, several mechanisms favor the expansion of the functional β‐cell mass during pregnancy or in obese individuals to compensate for insulin resistance of peripheral tissues. Type 2 diabetes develops if the functional β‐cell mass fails to adapt to cover the increased insulin needs. Lastly, aging and β‐cell senescence can reduce the capacity to compensate for insulin resistance.


Figure 2. Relative amounts of RNA transcripts in human and mouse cells. Pie chart representing the proportion of different RNA classes compared to the total number of annotated genes in (A) human (60,603 genes) or (B) mouse (55,487 genes). Data obtained from Gencode 31. Abbreviations: lncRNAs, long‐noncoding ribonucleic acids; miRNAs, micro‐ribonucleic acids; snoRNAs, small nucleolar ribonucleic acids; snRNAs, small nuclear ribonucleic acids; ncRNAs, noncoding ribonucleic acids.


Figure 3. Classification of RNAs. RNA molecules can be divided into two categories, depending on their ability to code (coding RNA) or not (noncoding RNA) for proteins. Noncoding RNA transcripts are classified based on their function (rRNA, ribosomal ribonucleic acid; tRNA, transfer ribonucleic acid) or on their length (shorter or longer than 200 nucleotides). The short RNA families include snoRNAs (small nucleolar ribonucleic acids), snRNAs (small nuclear ribonucleic acids), siRNAs (small interfering ribonucleic acids), miRNAs (micro‐ribonucleic acids), and piRNAs (PIWI‐interacting ribonucleic acids). The long‐noncoding ribonucleic acid (lncRNA) family is further subdivided based on the shape of the RNA molecules: linear lncRNA or circular ribonucleic acid (circRNA). Of note, tRNA molecules can be cleaved to generate fragments (tRF) that share some properties with other short ncRNAs.


Figure 4. Generation and classification of tRFs. Endonucleic cleavage of mature tRNAs generates a diverse range of tRFs. Various endonucleases including Dicer generate short tRFs (12–20 nucleotides) at either arms of the tRNAs. Alternatively, angiogenin cleaves tRNAs at the anticodon loop, generating tRNA halves (32–50 nucleotides, also known as tiRNAs). A double cleavage along the length of tRNAs can generate internal tRNA fragments (16 nucleotides or longer, also known as i‐tRFs).


Figure 5. Classification of lncRNAs based on their genomic proximity to protein‐coding genes. (A) Long intergenic noncoding ribonucleic acids (lincRNAs) are located in intergenic regions. They are situated at more than 1 kb distance from the nearest protein‐coding genes. (B) The other classes of long noncoding ribonucleic acids (lncRNAs) are located in the vicinity of protein‐coding genes and are named based on how their exons are positioned on the genome with respect to the exons of the mRNA and on the direction of transcription: overlapping, intronic, cis‐antisense, or bidirectional.


Figure 6. Examples of mode of action of lncRNAs in β‐cells. (A) The lncRNA PLUTO acts on 3D chromatin organization to favor the transcription of PDX1 by bringing in close proximity the PDX1 promoter with its enhancer cluster. (B) The lncRNA Meg3 inhibits EZH2‐mediated methylation of Rad21, Smc3, and Sin3α promoters, triggering the expression of these transcription factors and, therefore, resulting in the inhibition of MafA expression. (C) The lncRNA H19 sequesters let‐7 members to prevent the repression of target genes of these miRNAs, leading to activation of the PI3K/AKT pathway. Abbreviations: lncRNA, long noncoding ribonucleic acid; miRNA, micro‐ribonucleic acid; PI3K, phosphatidylinositol 3‐kinase.


Figure 7. Formation of circular RNAs in eukaryotic cells. Eukaryotic circRNAs can be generated from introns (gray) and/or exons (colored) of pre‐mRNAs. Circular intronic RNAs (left) arise from introns circularized at the 5′ and branchpoint (bp) nucleotides by a 2′ to 5′ junction during linear splicing. These branched circular introns have a linear 3′ tail and are known as lariats. Intron lariats can be debranched and rapidly degraded or escape debranching, lose their tail, and turn into stable circular intronic RNAs. Instead, circular exonic and exonic‐intronic RNAs (right) can contain one or more exons and/or introns and are produced by backsplicing of an upstream 3′ splice site and a downstream 5′ splice site circularized by a 3′ to 5′ junction.


Figure 8. Exosome cross talk in the context of type 1 and type 2 diabetes. (A) In the context of T1D, islet mesenchymal stem cells (i‐MSC) and β‐cells secrete exosomes that activate T‐ and B‐cells. Pancreatic islet cells produce exosomes that can horizontally transfer genetic material to adjacent islet cells and endothelial cells. Infiltrated T‐cells transfer specific miRNAs via exosomes to β‐cells. (B) In the context of T2D, muscle and hepatic exosomes deliver miRNAs to pancreatic islet cells. Exosomes secreted from adipose tissue macrophages (ATMs) transfer miRNAs to insulin target tissues. Adipose tissue release exosomes containing miRNAs to liver and skeletal muscle. (A,B) Pancreatic islet exosomes and ncRNAs that are released in the blood stream represent potential biomarkers for T1D and T2D.
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Article Title: Roles of Noncoding RNAs in Islet Biology
 

How to Cite

Claudiane Guay, Cécile Jacovetti, Mustafa Bilal Bayazit, Flora Brozzi, Adriana Rodriguez‐Trejo, Kejing Wu, Romano Regazzi. Roles of Noncoding RNAs in Islet Biology. Compr Physiol 2020, 10: 893-932. doi: 10.1002/cphy.c190032