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

Dhawan, Sangeeta; Georgia, Senta; Tschen, Shuen-Ing; Fan, Guoping; Bhushan, Anil

doi:10.1016/j.devcel.2011.03.012

Cited by 230 publications

(253 citation statements)

References 39 publications

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“…Cell plasticity has been intensively investigated in adult pancreatic endocrine cells. Lineage tracing analyses of adult pancreatic cells for various in vivo conditions clearly demonstrate that conversion between different pancreatic cell types occurs in adults through changes in the expression of transcription factors that are critical for endocrine cell differentiation [3][4][5][6][7][8]. These findings are supported by studies reporting that the forced expression of transcription factors convert cell types [9][10][11].…”

Section: Introductionsupporting

confidence: 75%

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MafA is critical for maintenance of the mature beta cell phenotype in mice

2014

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Aims/hypothesis The plasticity of adult somatic cells allows for their dedifferentiation or conversion to different cell types, although the relevance of this to disease remains elusive. Perturbation of beta cell identity leading to dedifferentiation may be implicated in the compromised functions of beta cells in diabetes, which is a current topic of islet research. This study aims to investigate whether or not v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker, is involved in maintaining mature beta cell phenotypes. Methods The fate and gene expression of beta cells were analysed in Mafa knockout (KO) mice and mouse models of diabetes in which the expression of MafA was reduced in the majority of beta cells. Results Loss of MafA reduced the beta to alpha cell ratio in pancreatic islets without elevating blood glucose to diabetic levels. Lineage tracing analyses showed reduced/lost expression of insulin in most beta cells, with a minority of the former beta cells converted to glucagon-expressing cells in Mafa KO mice. The upregulation of genes that are normally repressed in mature beta cells or transcription factors that are transiently expressed in endocrine progenitors was identified in Mafa KO islets as a hallmark of dedifferentiation. The compromised beta cells in db/db and multiple low-dose streptozotocin mice underwent similar dedifferentiation with expression of Mafb, which is expressed in immature beta cells. Conclusions/interpretation The maturation factor MafA is critical for the homeostasis of mature beta cells and regulates cell plasticity. The loss of MafA in beta cells leads to a deeper loss of cell identity, which is implicated in diabetes pathology.

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Section: Introductionsupporting

confidence: 75%

“…The expression of DNA methyltransferases was analysed because the loss of DNA methyltransferase (DNMT) 1 or DNMT3a results in a conversion from beta cell to alpha cell [4,5]. Dnmt1 and Dnmt3a expression was decreased in the Mafa KO islets (Fig.…”

Section: Resultsmentioning

confidence: 99%

MafA is critical for maintenance of the mature beta cell phenotype in mice

2014

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“…19,20 Vice versa, Arista-less-related homeobox (ARX), a master gene for a-cells, is normally methylated and repressed in pancreatic b-cells by DNMT1 with concomitant preservation of b-cell identity. 21 Therefore, it has been proposed that b-cell identity depends on the epigenetically controlled antagonistic activities of PAX4 and ARX, but the fine tuning mechanisms are still unclear. 21 Beside passive demethylation (inhibition of DNMTs), active demethylating mechanisms involving TET enzymes can also be involved in the correct development of pancreatic islets.…”

Section: B-cell Development and Functionmentioning

confidence: 99%

“…21 Therefore, it has been proposed that b-cell identity depends on the epigenetically controlled antagonistic activities of PAX4 and ARX, but the fine tuning mechanisms are still unclear. 21 Beside passive demethylation (inhibition of DNMTs), active demethylating mechanisms involving TET enzymes can also be involved in the correct development of pancreatic islets. 10 A relatively recent study on heterozygous miR-26a transgenic mice showed reduced expression of TET2 during islet postnatal differentiation and increased postnatal islet cell number.…”

Section: B-cell Development and Functionmentioning

confidence: 99%

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

et al. 2017

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Epigenetics is involved in the altered expression of gene networks that underlie insulin resistance and insufficiency. Major genes controlling b-cell differentiation and function, such as PAX4, PDX1, and GLP1 receptor, are epigenetically controlled. Epigenetics can cause insulin resistance through immunomediated pro-inflammatory actions related to several factors, such as NF-kB, osteopontin, and Toll-like receptors. Hereafter, we provide a critical and comprehensive summary on this topic with a particular emphasis on translational and clinical aspects. We discuss the effect of epigenetics on b-cell regeneration for cell replacement therapy, the emerging bioinformatics approaches for analyzing the epigenetic contribution to type 2 diabetes mellitus (T2DM), the epigenetic core of the transgenerational inheritance hypothesis in T2DM, and the epigenetic clinical trials on T2DM. Therefore, prevention or reversion of the epigenetic changes occurring during T2DM development may reduce the individual and societal burden of the disease.

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“…First, epigenetic regulators can decide the reprogramming process by themselves. For example, pancreatic beta cells can be reprogrammed into alpha cells by DNA methyltransferase Dnmt1 deficiency (Dhawan et al, 2011). Second, epigenetic regulators can interact with exogenous factors to re-activate or suppress related gene expression.…”

Section: Epigenetic Regulatorsmentioning

confidence: 99%

Direct reprogramming of somatic cells: an update

Pham

2015

Biomed Res Ther

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Abstract-Direct epigenetic reprogramming is a technique that converts a differentiated adult cell into another differentiated cell-such fibroblasts to cardiomyocytes-without passage through an undifferentiated pluripotent stage. This novel technology is opening doors in biological research and regenerative medicine. Some preliminary studies about direct reprogramming started in the 1980s when differentiated adult cells could be converted into other differentiated cells by overexpressing transcription-factor genes. These studies also showed that differentiated cells have plasticity. Direct reprogramming can be a powerful tool in biological research and regenerative medicine, especially the new frontier of personalized medicine. This review aims to summarize all direct reprogramming studies of somatic cells by master control genes as well as potential applications of these techniques in research and treatment of selected human diseases.

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

Cited by 230 publications

References 39 publications

MafA is critical for maintenance of the mature beta cell phenotype in mice

MafA is critical for maintenance of the mature beta cell phenotype in mice

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

Direct reprogramming of somatic cells: an update

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