PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration

Zhu, Yaxi; Liu, Qian; Zhou, Zhiguang; Ikeda, Yasuhiro

doi:10.1186/s13287-017-0694-z

Cited by 239 publications

(189 citation statements)

References 46 publications

(54 reference statements)

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“…Pancreas/duodenum homeobox protein 1 (PDX1) is the master transcription factor that controls pancreatic β cell maturation and function by regulating the expression of several key genes including glucokinase and insulin genes, and a decrease in PDX1 expression is the key characteristics of pancreatic β dysfunction. 21,22 Transcription factor forkhead box protein A2 (FOXA2), also known as hepatocyte nuclear factor 3-beta (HNF-3β), is also critical for maintaining pancreatic cell functions by regulating PDX1 expression. [23][24][25][26][27] Glucose-induced DNA methylation in the promoter region and miRNAs such as miR-141, miR-124a, and miR-342 inhibit FOXA2 expression in pancreatic β cells.…”

Section: Introductionmentioning

confidence: 99%

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

et al. 2020

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So far, the mechanism that links mitochondrial dysfunction to PDX1 inhibition in the pathogenesis of pancreatic β cell dysfunction under diabetic condition remains largely unclear. This study determined the role of mitochondrial protein FAM3A in regulating PDX1 expression in pancreatic β cells using gain‐ and loss‐of function methods in vitro and in vivo. Within pancreas, FAM3A is highly expressed in β, α, δ, and pp cells of islets. Islet FAM3A expression was correlated with insulin expression under physiological and diabetic conditions. Mice with specific knockout of FAM3A in islet β cells exhibited markedly blunted insulin secretion and glucose intolerance. FAM3A‐deficient islets showed significant decrease in PDX1 expression, and insulin expression and secretion. FAM3A overexpression upregulated PDX1 and insulin expressions, and augmented insulin secretion in cultured islets and β cells. Mechanistically, FAM3A enhanced ATP production to elevate cellular Ca2+ level and promote insulin secretion. Furthermore, FAM3A‐induced ATP release activated CaM to function as a co‐activator of FOXA2, stimulating PDX1 gene transcription. In conclusion, FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic β cells. Inhibition of FAM3A will trigger mitochondrial dysfunction to repress PDX1 and insulin expressions.

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Section: Introductionmentioning

confidence: 99%

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

et al. 2020

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“…Four different types of islet cells (alpha, beta, delta, and pancreatic polypeptide), as well as endocrine precursor cells, were shown as absent in NEUROG3-deficient mice, which died postnatally from diabetes [23].…”

Section: Discussionmentioning

confidence: 97%

Exposure to PM_2.5 during pregnancy or lactation increases methylation while reducing the expression of Pdx1 and NEUROG3 in mouse pancreatic islets

Lima

Boico

Peruca

et al. 2019

Preprint

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Air pollution is comprised of several substances, including particulate matter (PM). Exposure to air pollution may trigger alterations in DNA methylation thus modifying gene expression patterns. This phenomenon is likely to mediate the relationship between exposure to air pollution and adverse health effects. The purpose of this study was analyzing the effects of exposure to PM 2.5 during pregnancy or lactation and whether it would cause multigenerational epigenetic alterations in the promoter region of the genes Pdx1 and NEUROG3 within mouse pancreatic islets. Our results show that maternal exposure to PM 2.5 led to an elevation in blood glucose levels within the two following generations (F1 and F2). There was also an increase in DNA methylation in the aforementioned promoter regions accompanied by reduced gene expression in generations F1 and F2 upon F0 exposure to PM 2.5 during pregnancy. These data suggest that maternal exposure to PM 2.5 from air pollution, particularly during pregnancy, may lead to a multigenerational and lifelong negative impact on glucose homeostasis mediated by an increase in DNA methylation within the promoter region of the genes Pdx1 and NEUROG3 in pancreatic islets.

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“…is exclusive to β-cells and α-cells, respectively. PDX1 drives differentiation of the early pancreatic epithelium and maintains the hormone-secreting phenotype of β-cells 37,38 . Our data showed hypomethylation within promoter and gene-body of PDX1 in the β-like samples, while maintaining a hypermethylated state in α-like samples.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

Simon

Riemer

Detjen

et al. 2020

Preprint

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Pancreatic Neuroendocrine Neoplasms (PanNENs) comprise a rare and heterogeneous group of tumors derived from neuroendocrine cells of the pancreas. Despite recent genetic and epigenetic characterization, biomarkers for improved patient stratification and personalized therapy are sparse and targeted therapies, including the mTOR inhibitor Everolimus, have shown limited success. To better define PanNENs tumors we performed multi-omic analyses on 59 tumors with varying grades (NET G1, NET G2, NET G3 and NEC), combining mutational profiling with epigenetic analysis and targeted proteomics. An unsupervised approach using DNA methylation profiles uncovered two major subgroups in PanNENs resembling α-like and β-like cells. DNA copy number analysis further divided the α-like subgroup into two distinct groups, indicating differential mechanisms of tumorigenesis from α-cells. β-like tumors however showed two distinct groups at the epigenetic level and suggest NET G3/NEC samples are of β-cell origin.DNA mutation profiling clearly separated α and β-cell derived PanNENs, whereby only αlike tumors had mutations within MEN1/DAXX/ATRX tumor suppressor genes. Targeted proteomic analysis further indicated overexpression of distinct components of the mTOR pathway. Our data provide further insights into the potential mechanisms behind PanNEN heterogeneity and form a basis for future diagnostic and therapy relevant patient stratification.

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PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration

Cited by 239 publications

References 46 publications

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

Exposure to PM_2.5 during pregnancy or lactation increases methylation while reducing the expression of Pdx1 and NEUROG3 in mouse pancreatic islets

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

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PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration

Cited by 239 publications

References 46 publications

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

Exposure to PM2.5 during pregnancy or lactation increases methylation while reducing the expression of Pdx1 and NEUROG3 in mouse pancreatic islets

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

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Exposure to PM_2.5 during pregnancy or lactation increases methylation while reducing the expression of Pdx1 and NEUROG3 in mouse pancreatic islets