Nkx2.2 repressor complex regulates islet β-cell specification and prevents β-to-α-cell reprogramming

Papizan, James B.; Singer, Ruth A.; Tschen, Shuen-Ing; Dhawan, Sangeeta; Friel, Jessica M.; Hipkens, Susan B.; Magnuson, Mark A.; Bhushan, Anil; Sussel, Lori

doi:10.1101/gad.173039.111

Cited by 183 publications

(208 citation statements)

References 60 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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“…Several recent reports demonstrate that forced expression of lineageinappropriate transcription factors causes islet cells to switch identity (Collombat et al, 2007;Collombat et al, 2009;Gao et al, 2014;Papizan et al, 2011;, which has been attributed to the similar chromatin states of alpha and beta cells (Bramswig et al, 2013). This establishes that beta cells can arise from nonbeta endocrine cells in the islet via direct transdifferentiation.…”

Section: Introductionmentioning

confidence: 92%

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

et al. 2017

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“…their ability to transdifferentiate to other cell types (JONAS et al 1999;PAPIZAN et al 2011;TALCHAI et al 2012;WANG et al 2014). …”

Section: Discussionmentioning

confidence: 99%

Genetic Drivers of Pancreatic Islet Function

et al. 2018

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The majority of gene loci that have been associated with type 2 diabetes play a role in pancreatic islet function. To evaluate the role of islet gene expression in the etiology of diabetes, we sensitized a genetically diverse mouse population with a Western diet high in fat (45%-kcal) and sucrose (34%) and carried out genome-wide association mapping of diabetes-related phenotypes. We quantified mRNA abundance in the islets and identified 18,820 expression quantitative trait loci. We applied mediation analysis to identify candidate causal driver genes at loci that affect the abundance of numerous transcripts. These include two genes previously associated with monogenic diabetes (PDX1 and HNF4A), as well as three genes with nominal association with diabetes-related traits in humans (FAM83E, IL6ST, and SAT2). We grouped transcripts into gene modules and mapped regulatory loci for modules enriched with transcripts specific for α-cells, and another specific for δ-cells. However, no single module enriched for β-cell-specific transcripts, suggesting heterogeneity of gene expression patterns within the β-cell population. A module enriched in transcripts associated with branched chain amino acid metabolism was the most strongly correlated with physiological traits that reflect insulin resistance. Although the mice in this study were not overtly diabetic, the analysis of pancreatic islet gene expression under dietary-induced stress enabled us to identify correlated variation in groups of genes that are functionally linked to diabetes-associated physiological traits. Our analysis suggests an expected degree of concordance between diabetes-associated loci in the mouse with those found in human populations and demonstrates how the mouse can provide evidence to support nominal associations found in human genome-wide association mapping.4

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Nkx2.2 repressor complex regulates islet β-cell specification and prevents β-to-α-cell reprogramming

Cited by 183 publications

References 60 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

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

Genetic Drivers of Pancreatic Islet Function

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