GLIS3: A Critical Transcription Factor in Islet β-Cell Generation

Understanding of pancreatic islet biology has greatly increased over the past few decades based in part on an increased understanding of the transcription factors that guide this process. One such transcription factor that has been increasingly tied to both β-cell development and the development of diabetes in humans is GLIS3. Genetic deletion of GLIS3 in mice and humans induces neonatal diabetes, while single nucleotide polymorphisms (SNPs) in GLIS3 have been associated with both Type 1 and Type 2 diabetes. As a significant progress has been made in understanding some of GLIS3’s roles in pancreas development and diabetes, we sought to compare current knowledge on GLIS3 within the pancreas to that of other islet enriched transcription factors. While GLIS3 appears to regulate similar genes and pathways to other transcription factors, its unique roles in β-cell development and maturation make it a key target for future studies and therapy.

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Role for Activating Transcription Factor 3 in Stress-Induced β-Cell Apoptosis

Molecular and Cellular Biology ◽

10.1128/mcb.24.13.5721-5732.2004 ◽

2004 ◽

Vol 24 (13) ◽

pp. 5721-5732 ◽

Cited By ~ 220

Author(s):

Matthew G. Hartman ◽

Dan Lu ◽

Mi-Lyang Kim ◽

Gary J. Kociba ◽

Tala Shukri ◽

...

Keyword(s):

Nitric Oxide ◽

Type 2 Diabetes ◽

Transcription Factor ◽

Cell Apoptosis ◽

Activating Transcription Factor 3 ◽

Β Cells ◽

Β Cell ◽

Activating Transcription Factor

ABSTRACT Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a member of the ATF/CREB family of transcription factors. However, the physiological significance of ATF3 induction by stress signals is not clear. In this report, we describe several lines of evidence supporting a role of ATF3 in stress-induced β-cell apoptosis. First, ATF3 is induced in β cells by signals relevant to β-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-κB and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in β cells develop abnormal islets and defects secondary to β-cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine- or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced β-cell apoptosis.

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Emerging roles of GLIS3 in neonatal diabetes, type 1 and type 2 diabetes

Journal of Molecular Endocrinology ◽

10.1530/jme-16-0232 ◽

2017 ◽

Vol 58 (2) ◽

pp. R73-R85 ◽

Cited By ~ 15

Author(s):

Xianjie Wen ◽

Yisheng Yang

Keyword(s):

Type 2 Diabetes ◽

Zinc Finger Protein ◽

Association Studies ◽

Protein A ◽

Neonatal Diabetes ◽

Genome Wide Association Studies ◽

Β Cell ◽

Ductal Cells

GLI-similar 3 (GLIS3), a member of the Krüppel-like zinc finger protein subfamily, is predominantly expressed in the pancreas, thyroid and kidney. Glis3 mRNA can be initially detected in mouse pancreas at embryonic day 11.5 and is largely restricted to β cells, pancreatic polypeptide-expressing cells, as well as ductal cells at later stage of pancreas development. Mutations in GLIS3 cause a neonatal diabetes syndrome, characterized by neonatal diabetes, congenital hypothyroidism and polycystic kidney. Importantly, genome-wide association studies showed that variations of GLIS3 are strongly associated with both type 1 diabetes (T1D) and type 2 diabetes (T2D) in multiple populations. GLIS3 cooperates with pancreatic and duodenal homeobox 1 (PDX1), v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MAFA), as well as neurogenic differentiation 1 (NEUROD1) and potently controls insulin gene transcription. GLIS3 also plays a role in β cell survival and likely in insulin secretion. Any perturbation of these functions may underlie all three forms of diabetes. GLIS3, synergistically with hepatocyte nuclear factor 6 (HNF6) and forkhead box A2 (FOXA2), controls fetal islet differentiation via transactivating neurogenin 3 (NGN3) and impairment of this function leads to neonatal diabetes. In addition, GLIS3 is also required for the compensatory β cell proliferation and mass expansion in response to insulin resistance, which if disrupted may predispose to T2D. The increasing understanding of the mechanisms of GLIS3 in β cell development, survival and function maintenance will provide new insights into disease pathogenesis and potential therapeutic target identification to combat diabetes.

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Crosstalk between Macrophages and Pancreatic β-Cells in Islet Development, Homeostasis and Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22041765 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1765

Author(s):

Cristina Cosentino ◽

Romano Regazzi

Keyword(s):

Current Knowledge ◽

Low Grade ◽

Β Cells ◽

Β Cell ◽

Physiological Conditions ◽

Close Proximity ◽

Inflammatory Profile

Macrophages are highly heterogeneous and plastic immune cells with peculiar characteristics dependent on their origin and microenvironment. Following pathogen infection or damage, circulating monocytes can be recruited in different tissues where they differentiate into macrophages. Stimuli present in the surrounding milieu induce the polarisation of macrophages towards a pro-inflammatory or anti-inflammatory profile, mediating inflammatory or homeostatic responses, respectively. However, macrophages can also derive from embryonic hematopoietic precursors and reside in specific tissues, actively participating in the development and the homeostasis in physiological conditions. Pancreatic islet resident macrophages are present from the prenatal stages onwards and show specific surface markers and functions. They localise in close proximity to β-cells, being exquisite sensors of their secretory ability and viability. Over the years, the crucial role of macrophages in β-cell differentiation and homeostasis has been highlighted. In addition, macrophages are emerging as central players in the initiation of autoimmune insulitis in type 1 diabetes and in the low-grade chronic inflammation characteristic of obesity and type 2 diabetes pathogenesis. The present work reviews the current knowledge in the field, with a particular focus on the mechanisms of communication between β-cells and macrophages that have been described so far.

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Shiga taxin type 2 but not type 1 induces interleukin-12 expression from peripheral blood mononuclear cells via activated nuclear transcription factor-kB

Gastroenterology ◽

10.1016/s0016-5085(01)81612-7 ◽

2001 ◽

Vol 120 (5) ◽

pp. A324-A324

Author(s):

M TATEWAKI ◽

H NAKAO ◽

H NOGAMI ◽

E HOSHINO ◽

H MOTEGI ◽

...

Keyword(s):

Transcription Factor ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Interleukin 12 ◽

Peripheral Blood Mononuclear ◽

Nuclear Transcription Factor ◽

Blood Mononuclear Cells

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The pseudomalachite-ludjibaite-reichenbachite conundrum: OD description

The Canadian Mineralogist ◽

10.3749/canmin.1900016 ◽

2019 ◽

Vol 57 (5) ◽

pp. 571-581

Author(s):

Emil Makovicky

Keyword(s):

Crystal Structures ◽

Current Knowledge ◽

The Other ◽

Crystal Chemical ◽

Layer System ◽

Coordination Polyhedra

Abstract Crystal structures of the three polymorphs of Cu5(PO4)2(OH)4, namely pseudomalachite, ludjibaite, and reichenbachite, can be described as being composed of rods perpendicular to their crystal-chemical layering. Two different sorts of rods can be defined. Type 1 rods share rows of Cu coordination polyhedra, forming a series of slabs. Slab boundaries and slab interiors represent alternating geometric OD layers of two kinds, with layer symmetries close to P21/m and , which make up two different stacking schemes of geometric OD layers in the structures of ludjibaite and pseudomalachite. Such OD layers, however, are not developed in reichenbachite. Type 2 rods are defined as having columns of PO4 tetrahedra in the corners of the rods. In the Type 2 slabs composed of these rods, geometric Pg OD layers of glide-arrayed tetrahedra alternate with more complex OD layers; in ludjibaite this system of layers is oriented diagonally with respect to the Type 1 OD layer system. Two different OD stackings of Type 2 OD layers form the ludjibaite and reichenbachite structures but not that of pseudomalachite. Thus, ludjibaite might form disordered intergrowths with either of the other two members of the triplet but reichenbachite and pseudomalachite should not form oriented intergrowths. Current knowledge concerning formation of the three polymorphs is considered.

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Subnuclear compartmentalization of sequence-specific transcription factors and regulation of eukaryotic gene expression

Biochemistry and Cell Biology ◽

10.1139/o05-062 ◽

2005 ◽

Vol 83 (4) ◽

pp. 535-547 ◽

Cited By ~ 7

Author(s):

Gareth N Corry ◽

D Alan Underhill

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Transcription Factors ◽

Transcriptional Activation ◽

Current Knowledge ◽

Nuclear Architecture ◽

Subnuclear Localization ◽

Modular Structures

To date, the majority of the research regarding eukaryotic transcription factors has focused on characterizing their function primarily through in vitro methods. These studies have revealed that transcription factors are essentially modular structures, containing separate regions that participate in such activities as DNA binding, protein–protein interaction, and transcriptional activation or repression. To fully comprehend the behavior of a given transcription factor, however, these domains must be analyzed in the context of the entire protein, and in certain cases the context of a multiprotein complex. Furthermore, it must be appreciated that transcription factors function in the nucleus, where they must contend with a variety of factors, including the nuclear architecture, chromatin domains, chromosome territories, and cell-cycle-associated processes. Recent examinations of transcription factors in the nucleus have clarified the behavior of these proteins in vivo and have increased our understanding of how gene expression is regulated in eukaryotes. Here, we review the current knowledge regarding sequence-specific transcription factor compartmentalization within the nucleus and discuss its impact on the regulation of such processes as activation or repression of gene expression and interaction with coregulatory factors.Key words: transcription, subnuclear localization, chromatin, gene expression, nuclear architecture.

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The Landscape of microRNAs in βCell: Between Phenotype Maintenance and Protection

International Journal of Molecular Sciences ◽

10.3390/ijms22020803 ◽

2021 ◽

Vol 22 (2) ◽

pp. 803

Author(s):

Giuseppina Emanuela Grieco ◽

Noemi Brusco ◽

Giada Licata ◽

Daniela Fignani ◽

Caterina Formichi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Metabolic Disorders ◽

Molecular Mechanisms ◽

Β Cell ◽

Physiological Mechanisms ◽

Effective Strategies ◽

Chronic Hyperglycaemia ◽

Shed Light

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia mainly due to pancreatic β cell death and/or dysfunction, caused by several types of stress such as glucotoxicity, lipotoxicity and inflammation. Different patho-physiological mechanisms driving β cell response to these stresses are tightly regulated by microRNAs (miRNAs), a class of negative regulators of gene expression, involved in pathogenic mechanisms occurring in diabetes and in its complications. In this review, we aim to shed light on the most important miRNAs regulating the maintenance and the robustness of β cell identity, as well as on those miRNAs involved in the pathogenesis of the two main forms of diabetes mellitus, i.e., type 1 and type 2 diabetes. Additionally, we acknowledge that the understanding of miRNAs-regulated molecular mechanisms is fundamental in order to develop specific and effective strategies based on miRNAs as therapeutic targets, employing innovative molecules.

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NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas

International Journal of Molecular Sciences ◽

10.3390/ijms22136713 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6713

Author(s):

Romana Bohuslavova ◽

Ondrej Smolik ◽

Jessica Malfatti ◽

Zuzana Berkova ◽

Zaneta Novakova ◽

...

Keyword(s):

Transcription Factor ◽

Cell Fate ◽

Cell Mass ◽

Neonatal Diabetes ◽

Diabetes Research ◽

Pancreas Development ◽

Β Cells ◽

Β Cell ◽

Pancreatic Islet Cell ◽

Endocrine Differentiation

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.

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Non-Coding RNA in Pancreas and β-Cell Development

Non-Coding RNA ◽

10.3390/ncrna4040041 ◽

2018 ◽

Vol 4 (4) ◽

pp. 41 ◽

Cited By ~ 7

Author(s):

Wilson K. M. Wong ◽

Anja E. Sørensen ◽

Mugdha V. Joglekar ◽

Anand A. Hardikar ◽

Louise T. Dalgaard

Keyword(s):

Cell Function ◽

Islet Cells ◽

Current Knowledge ◽

Cell Development ◽

Pancreas Development ◽

Β Cell ◽

Neighboring Gene ◽

Non Coding Rnas ◽

And Function

In this review, we provide an overview of the current knowledge on the role of different classes of non-coding RNAs for islet and β-cell development, maturation and function. MicroRNAs (miRNAs), a prominent class of small RNAs, have been investigated for more than two decades and patterns of the roles of different miRNAs in pancreatic fetal development, islet and β-cell maturation and function are now emerging. Specific miRNAs are dynamically regulated throughout the period of pancreas development, during islet and β-cell differentiation as well as in the perinatal period, where a burst of β-cell replication takes place. The role of long non-coding RNAs (lncRNA) in islet and β-cells is less investigated than for miRNAs, but knowledge is increasing rapidly. The advent of ultra-deep RNA sequencing has enabled the identification of highly islet- or β-cell-selective lncRNA transcripts expressed at low levels. Their roles in islet cells are currently only characterized for a few of these lncRNAs, and these are often associated with β-cell super-enhancers and regulate neighboring gene activity. Moreover, ncRNAs present in imprinted regions are involved in pancreas development and β-cell function. Altogether, these observations support significant and important actions of ncRNAs in β-cell development and function.

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