Islet Epigenetic Impacts on β‐Cell Identity and Function

The progression of Type 2 diabetes is accompanied by diminishing islet β-cell mass and function. It has been proposed that β-cells are lost not only through apoptosis, but also by dedifferentiating into progenitor-like cells. There is therefore much interest in the mechanisms which define and maintain β-cell identity. The advent of genome-wide analyses of chromatin modifications has highlighted the role of epigenetic factors in determining cell identity. There is also evidence from both human populations and animal models for an epigenetic component in susceptibility to Type 2 diabetes. The mechanisms responsible for defining the epigenetic landscape in individual cell types are poorly understood, but there is growing evidence of a role for lncRNAs (long non-coding RNAs) in this process. In the present paper, we discuss some of the mechanisms through which lncRNAs may contribute to β-cell identity and Type 2 diabetes risk.

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Loss of β-cell identity and diabetic phenotype in mice caused by disruption of CNOT3-dependent mRNA deadenylation

Communications Biology ◽

10.1038/s42003-020-01201-y ◽

2020 ◽

Vol 3 (1) ◽

Cited By ~ 1

Author(s):

Dina Mostafa ◽

Akiko Yanagiya ◽

Eleni Georgiadou ◽

Yibo Wu ◽

Theodoros Stylianides ◽

...

Keyword(s):

Cell Function ◽

Cell Mass ◽

Cell Maturation ◽

Β Cells ◽

Β Cell ◽

Cell Identity ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Β Cell Function ◽

And Function

AbstractPancreatic β-cells are responsible for production and secretion of insulin in response to increasing blood glucose levels. Defects in β-cell function lead to hyperglycemia and diabetes mellitus. Here, we show that CNOT3, a CCR4–NOT deadenylase complex subunit, is dysregulated in islets in diabetic db/db mice, and that it is essential for murine β cell maturation and identity. Mice with β cell-specific Cnot3 deletion (Cnot3βKO) exhibit impaired glucose tolerance, decreased β cell mass, and they gradually develop diabetes. Cnot3βKO islets display decreased expression of key regulators of β cell maturation and function. Moreover, they show an increase of progenitor cell markers, β cell-disallowed genes, and genes relevant to altered β cell function. Cnot3βKO islets exhibit altered deadenylation and increased mRNA stability, partly accounting for the increased expression of those genes. Together, these data reveal that CNOT3-mediated mRNA deadenylation and decay constitute previously unsuspected post-transcriptional mechanisms essential for β cell identity.

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Tead1 Reciprocally Regulates Adult β-Cell Proliferation and Function to Maintain Glucose Homeostasis

SSRN Electronic Journal ◽

10.2139/ssrn.3704009 ◽

2020 ◽

Author(s):

Jeongkyung Lee ◽

Ruya Liu ◽

Byung S. Kim ◽

Yiqun Zhang ◽

Feng Li ◽

...

Keyword(s):

Cell Proliferation ◽

Glucose Homeostasis ◽

Β Cell ◽

And Function

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Cadherins in early neural development

Cellular and Molecular Life Sciences ◽

10.1007/s00018-021-03815-9 ◽

2021 ◽

Author(s):

Karolina Punovuori ◽

Mattias Malaguti ◽

Sally Lowell

Keyword(s):

Adhesion Molecules ◽

Cell Fate ◽

Neural Development ◽

Ex Vivo ◽

Directed Differentiation ◽

Culture Dish ◽

Cell Identity ◽

Cell Fate Decisions ◽

Neural Tissues ◽

And Function

AbstractDuring early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type” (Waddington in Nature 183: 1654–1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772–774, 1988; Lander in Cell 144: 955–969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

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Pancreatic β Cell Identity Is Maintained by DNA Methylation-Mediated Repression of Arx

Developmental Cell ◽

10.1016/j.devcel.2011.03.012 ◽

2011 ◽

Vol 20 (4) ◽

pp. 419-429 ◽

Cited By ~ 170

Author(s):

Sangeeta Dhawan ◽

Senta Georgia ◽

Shuen-ing Tschen ◽

Guoping Fan ◽

Anil Bhushan

Keyword(s):

Dna Methylation ◽

Pancreatic Β Cell ◽

Β Cell ◽

Cell Identity

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Assessment of β-Cell Mass and α- and β-Cell Survival and Function by Arginine Stimulation in Human Autologous Islet Recipients

Diabetes ◽

10.2337/db14-0690 ◽

2014 ◽

Vol 64 (2) ◽

pp. 565-572 ◽

Cited By ~ 35

Author(s):

R. Paul Robertson ◽

Lindsey D. Bogachus ◽

Elizabeth Oseid ◽

Susan Parazzoli ◽

Mary Elizabeth Patti ◽

...

Keyword(s):

Cell Survival ◽

Cell Mass ◽

Β Cell ◽

And Function

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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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