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Review
. 2015 Sep;15(9):66.
doi: 10.1007/s11892-015-0635-0.

Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function

Michael L Stitzel  1 , Ina Kycia, Romy Kursawe, Duygu Ucar
Affiliations
Review

Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function

Michael L Stitzel et al. Curr Diab Rep. 2015 Sep.

Abstract

Islets of Langerhans contain multiple hormone-producing endocrine cells controlling glucose homeostasis. Transcription establishes and maintains islet cellular fates and identities. Genetic and environmental disruption of islet transcription triggers cellular dysfunction and disease. Early transcriptional regulation studies of specific islet genes, including insulin (INS) and the transcription factor PDX1, identified the first cis-regulatory DNA sequences and trans-acting factors governing islet function. Here, we review how human islet "omics" studies are reshaping our understanding of transcriptional regulation in islet (dys)function and diabetes. First, we highlight the expansion of islet transcript number, form, and function and of DNA transcriptional regulatory elements controlling their production. Next, we cover islet transcriptional effects of genetic and environmental perturbation. Finally, we discuss how these studies' emerging insights should empower our diabetes research community to build mechanistic understanding of diabetes pathophysiology and to equip clinicians with tailored, precision medicine options to prevent and treat islet dysfunction and diabetes.

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Figures

Figure 1
Figure 1. Transcriptomic and epigenomic features of normal and perturbed islets. (A) Transcriptional regulatory features in islets
Left; Open chromatin, islet transcription factor (TF) binding, and combinations of histone modification patterns (chromatin state) identify regulatory features in islets. Genes important for islet/beta cell identity and function (e.g., INS, KCNJ11, ABCC8, GCK) exhibit important epigenetic features, such as clustered sites of open chromatin (humps) and multiple islet TF binding (cotton balls), and extended enhancer (yellow bars) and promoter (red bars) chromatin state compared to features around a typical gene. Green bar indicates a “transcription elongation” state typically observed over non-specific, expressed genes. Right; 3D epigenomic analyses identify enhancer-target gene links, which can involve looping out/exclusion of the nearest gene (gray rectangle) on the linear genome to mediate 3D interactions between the enhancer (white circle). (B) Some genetic variants disrupt TF binding motifs (red “X”), abrogating protein binding (e.g., PDX1), reducing chromatin accessibility, and inactivating the gene. (C) Islets respond to perturbations such as oxidative stress, inflammation, and oxidative stress with nuclear translocation of several stress-responsive TFs (e.g., NF-KappaB, ATF4, XBP1(s), HIF1-alpha). These factors bind to new islet regulatory elements (triangles, circle) to activate the appropriate stress response genes (arrowhead). Islet TFs are inactivated and/or exported from the nucleus (red circles with slashes), abandoning their binding sites (rectangles) and leading to gene inactivation.
Figure 1
Figure 1. Transcriptomic and epigenomic features of normal and perturbed islets. (A) Transcriptional regulatory features in islets
Left; Open chromatin, islet transcription factor (TF) binding, and combinations of histone modification patterns (chromatin state) identify regulatory features in islets. Genes important for islet/beta cell identity and function (e.g., INS, KCNJ11, ABCC8, GCK) exhibit important epigenetic features, such as clustered sites of open chromatin (humps) and multiple islet TF binding (cotton balls), and extended enhancer (yellow bars) and promoter (red bars) chromatin state compared to features around a typical gene. Green bar indicates a “transcription elongation” state typically observed over non-specific, expressed genes. Right; 3D epigenomic analyses identify enhancer-target gene links, which can involve looping out/exclusion of the nearest gene (gray rectangle) on the linear genome to mediate 3D interactions between the enhancer (white circle). (B) Some genetic variants disrupt TF binding motifs (red “X”), abrogating protein binding (e.g., PDX1), reducing chromatin accessibility, and inactivating the gene. (C) Islets respond to perturbations such as oxidative stress, inflammation, and oxidative stress with nuclear translocation of several stress-responsive TFs (e.g., NF-KappaB, ATF4, XBP1(s), HIF1-alpha). These factors bind to new islet regulatory elements (triangles, circle) to activate the appropriate stress response genes (arrowhead). Islet TFs are inactivated and/or exported from the nucleus (red circles with slashes), abandoning their binding sites (rectangles) and leading to gene inactivation.
Figure 1
Figure 1. Transcriptomic and epigenomic features of normal and perturbed islets. (A) Transcriptional regulatory features in islets
Left; Open chromatin, islet transcription factor (TF) binding, and combinations of histone modification patterns (chromatin state) identify regulatory features in islets. Genes important for islet/beta cell identity and function (e.g., INS, KCNJ11, ABCC8, GCK) exhibit important epigenetic features, such as clustered sites of open chromatin (humps) and multiple islet TF binding (cotton balls), and extended enhancer (yellow bars) and promoter (red bars) chromatin state compared to features around a typical gene. Green bar indicates a “transcription elongation” state typically observed over non-specific, expressed genes. Right; 3D epigenomic analyses identify enhancer-target gene links, which can involve looping out/exclusion of the nearest gene (gray rectangle) on the linear genome to mediate 3D interactions between the enhancer (white circle). (B) Some genetic variants disrupt TF binding motifs (red “X”), abrogating protein binding (e.g., PDX1), reducing chromatin accessibility, and inactivating the gene. (C) Islets respond to perturbations such as oxidative stress, inflammation, and oxidative stress with nuclear translocation of several stress-responsive TFs (e.g., NF-KappaB, ATF4, XBP1(s), HIF1-alpha). These factors bind to new islet regulatory elements (triangles, circle) to activate the appropriate stress response genes (arrowhead). Islet TFs are inactivated and/or exported from the nucleus (red circles with slashes), abandoning their binding sites (rectangles) and leading to gene inactivation.
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