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Roles of Epigenetic Modifications in the Differentiation and Function of Pancreatic ?-Cells.

ABSTRACT: Diabetes, a metabolic disease with multiple causes characterized by high blood sugar, has become a public health problem. Hyperglycaemia is caused by deficiencies in insulin secretion, impairment of insulin function, or both. The insulin secreted by pancreatic ? cells is the only hormone in the body that lowers blood glucose levels and plays vital roles in maintaining glucose homeostasis. Therefore, investigation of the molecular mechanisms of pancreatic ? cell differentiation and function is necessary to elucidate the processes involved in the onset of diabetes. Although numerous studies have shown that transcriptional regulation is essential for the differentiation and function of pancreatic ? cells, increasing evidence indicates that epigenetic mechanisms participate in controlling the fate and regulation of these cells. Epigenetics involves heritable alterations in gene expression caused by DNA methylation, histone modification and non-coding RNA activity that does not result in DNA nucleotide sequence alterations. Recent research has revealed that a variety of epigenetic modifications play an important role in the development of diabetes. Here, we review the mechanisms by which epigenetic regulation affects ? cell differentiation and function.

SUBMITTER: Xu F

PROVIDER: S-EPMC7484512 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Roles of Epigenetic Modifications in the Differentiation and Function of Pancreatic β-Cells.

Xu Fei F Liu Jing J Na Lixin L Chen Linjun L

Frontiers in cell and developmental biology 20200828

Diabetes, a metabolic disease with multiple causes characterized by high blood sugar, has become a public health problem. Hyperglycaemia is caused by deficiencies in insulin secretion, impairment of insulin function, or both. The insulin secreted by pancreatic β cells is the only hormone in the body that lowers blood glucose levels and plays vital roles in maintaining glucose homeostasis. Therefore, investigation of the molecular mechanisms of pancreatic β cell differentiation and function is ne ...[more]

PMID: 32984307

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Project description:The polycomb repressor complex 2 molecule EZH2 is now known to play a role in essential cellular processes, namely, cell fate decisions, cell cycle regulation, senescence, cell differentiation, and cancer development/progression. EZH2 inhibitors have recently been developed; however, their effectiveness and underlying molecular mechanisms in many malignancies have not yet been elucidated in detail. Although the functional role of EZH2 in tumorigenesis in neuroblastoma (NB) has been investigated, mutations of EZH2 have not been reported. A Kaplan-Meier analysis on the event free survival and overall survival of NB patients indicated that the high expression of EZH2 correlated with an unfavorable prognosis. In order to elucidate the functional roles of EZH2 in NB tumorigenesis and its aggressiveness, we knocked down EZH2 in NB cell lines using lentivirus systems. The knockdown of EZH2 significantly induced NB cell differentiation, e.g., neurite extension, and the neuronal differentiation markers, NF68 and GAP43. EZH2 inhibitors also induced NB cell differentiation. We performed a comprehensive transcriptome analysis using Human Gene Expression Microarrays and found that NTRK1 (TrkA) is one of the EZH2-related suppression targets. The depletion of NTRK1 canceled EZH2 knockdown-induced NB cell differentiation. Our integrative methylome, transcriptome, and chromatin immunoprecipitation assays using NB cell lines and clinical samples clarified that the NTRK1 P1 and P2 promoter regions were regulated differently by DNA methylation and EZH2-related histone modifications. The NTRK1 transcript variants 1/2, which were regulated by EZH2-related H3K27me3 modifications at the P1 promoter region, were strongly expressed in favorable, but not unfavorable NB. The depletion and inhibition of EZH2 successfully induced NTRK1 transcripts and functional proteins. Collectively, these results indicate that EZH2 plays important roles in preventing the differentiation of NB cells and also that EZH2-related NTRK1 transcriptional regulation may be the key pathway for NB cell differentiation.

Dataset Information

Roles of Epigenetic Modifications in the Differentiation and Function of Pancreatic ?-Cells.

Publications

Roles of Epigenetic Modifications in the Differentiation and Function of Pancreatic β-Cells.

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