scholarly journals Foxa2 and MafA regulate islet-specific glucose-6-phosphatase catalytic subunit-related protein gene expression

2008 ◽  
Vol 41 (5) ◽  
pp. 315-328 ◽  
Author(s):  
Cyrus C Martin ◽  
Brian P Flemming ◽  
Yingda Wang ◽  
James K Oeser ◽  
Richard M O'Brien
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
Transcription Factors ◽  
Binding Sites ◽  
Fusion Gene ◽  
Fasting Blood Glucose ◽  
Catalytic Subunit ◽  
Related Protein ◽  
Min6 Cells

Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP/G6PC2) is a major autoantigen in both mouse and human type 1 diabetes. IGRP is selectively expressed in islet β cells and polymorphisms in the IGRP gene have recently been associated with variations in fasting blood glucose levels and cardiovascular-associated mortality in humans. Chromatin immunoprecipitation (ChIP) assays have shown that the IGRP promoter binds the islet-enriched transcription factors Pax-6 and BETA2. We show here, again using ChIP assays, that the IGRP promoter also binds the islet-enriched transcription factors MafA and Foxa2. Single binding sites for these factors were identified in the proximal IGRP promoter, mutation of which resulted in decreased IGRP fusion gene expression in βTC-3, Hamster insulinoma tumor (HIT), and Min6 cells. ChiP assays have shown that the islet-enriched transcription factor Pdx-1 also binds the IGRP promoter, but mutational analysis of four Pdx-1 binding sites in the proximal IGRP promoter revealed surprisingly little effect of Pdx-1 binding on IGRP fusion gene expression in βTC-3 cells. In contrast, in both HIT and Min6 cells mutation of these four Pdx-1 binding sites resulted in a ∼50% reduction in fusion gene expression. These data suggest that the same group of islet-enriched transcription factors, namely Pdx-1, Pax-6, MafA, BETA2, and Foxa2, directly or indirectly regulate expression of the two major autoantigens in type 1 diabetes.

scholarly journals Upstream stimulatory factor (USF) and neurogenic differentiation/beta-cell E box transactivator 2 (NeuroD/BETA2) contribute to islet-specific glucose-6-phosphatase catalytic-subunit-related protein (IGRP) gene expression

2003 ◽  
Vol 371 (3) ◽  
pp. 675-686 ◽  
Author(s):  
Cyrus C. MARTIN ◽  
Christina A. SVITEK ◽  
James K. OESER ◽  
Eva HENDERSON ◽  
Roland STEIN ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Fusion Gene ◽  
Catalytic Subunit ◽  
Related Protein ◽  
Upstream Stimulatory Factor ◽  
Factor Binding ◽  
E Box ◽  
Stimulatory Factor

Islet-specific glucose-6-phosphatase (G6Pase) catalytic-subunit-related protein (IGRP) is a homologue of the catalytic subunit of G6Pase, the enzyme that catalyses the final step of the gluconeogenic pathway. The analysis of IGRP-chloramphenicol acetyltransferase (CAT) fusion-gene expression through transient transfection of islet-derived βTC-3 cells revealed that multiple promoter regions, located between −306 and −97, are required for maximal IGRP-CAT fusion-gene expression. These regions correlated with trans-acting factor-binding sites in the IGRP promoter that were identified in βTC-3 cells in situ using the ligation-mediated PCR (LMPCR) footprinting technique. However, the LMPCR data also revealed additional trans-acting factor-binding sites located between −97 and +1 that overlap two E-box motifs, even though this region by itself conferred minimal fusion-gene expression. The data presented here show that these E-box motifs are important for IGRP promoter activity, but that their action is only manifest in the presence of distal promoter elements. Thus mutation of either E-box motif in the context of the −306 to +3 IGRP promoter region reduces fusion-gene expression. These two E-box motifs have distinct sequences and preferentially bind NeuroD/BETA2 neurogenic differentiation/β-cell E box transactivator 2 and upstream stimulatory factor (USF) in vitro, consistent with the binding of both factors to the IGRP promoter in situ, as determined using the chromatin-immunoprecipitation (ChIP) assay. Based on experiments using mutated IGRP promoter constructs, we propose a model to explain how the ubiquitously expressed USF could contribute to islet-specific IGRP gene expression.

scholarly journals Identification of CD4+ T Cell-Specific Epitopes of Islet-Specific Glucose-6-Phosphatase Catalytic Subunit-Related Protein: A Novel β Cell Autoantigen in Type 1 Diabetes

2005 ◽  
Vol 174 (9) ◽  
pp. 5306-5315 ◽  
Author(s):  
Rinee Mukherjee ◽  
Danielle Wagar ◽  
Tracey A. Stephens ◽  
Edwin Lee-Chan ◽  
Bhagirath Singh
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
Protein A ◽  
Catalytic Subunit ◽  
Cd4 T Cell ◽  
Related Protein ◽  
Β Cell

scholarly journals Deletion of the G6pc2 Gene Encoding the Islet-Specific Glucose-6-Phosphatase Catalytic Subunit–Related Protein Does Not Affect the Progression or Incidence of Type 1 Diabetes in NOD/ShiLtJ Mice

Diabetes ◽  
2011 ◽  
Vol 60 (11) ◽  
pp. 2922-2927 ◽  
Author(s):  
James K. Oeser ◽  
Vrajesh V. Parekh ◽  
Yingda Wang ◽  
Naresh K. Jegadeesh ◽  
Suparna A. Sarkar ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Catalytic Subunit ◽  
Related Protein ◽  
Gene Encoding

scholarly journals Peripheral Blood Monocyte Gene Expression Profile Clinically Stratifies Patients With Recent-Onset Type 1 Diabetes

Diabetes ◽  
2012 ◽  
Vol 61 (5) ◽  
pp. 1281-1290 ◽  
Author(s):  
Katharine M. Irvine ◽  
Patricia Gallego ◽  
Xiaoyu An ◽  
Shannon E. Best ◽  
Gethin Thomas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 1 Diabetes ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Peripheral Blood ◽  
Peripheral Blood Monocyte ◽  
Blood Monocyte ◽  
Recent Onset ◽  
Onset Type

scholarly journals Analysis of immune cell components and immune-related gene expression profiles in peripheral blood of patients with type 1 diabetes mellitus

2021 ◽  
Author(s):  
Jian Lin ◽  
Yuanhua Lu ◽  
Bizhou Wang ◽  
Ping Jiao ◽  
Jie Ma
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Type 1 Diabetes Mellitus ◽  
Nk Cells ◽  
Immune Cells ◽  
Support Vector ◽  
Hub Genes ◽  
Immune Related Genes

Abstract Background Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by severe loss of pancreatic β cells. Immune cells are key mediators of β cell destruction. This study attempted to investigate the role of immune cells and immune-related genes in the occurrence and development of T1DM. Methods The raw gene expression profile of the samples from 12 T1DM patients and 10 normal controls was obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by Limma package in R. The least absolute shrinkage and selection operator (LASSO) - support vector machines (SVM) were used to screen the hub genes. CIBERSORT algorithm was used to identify the different immune cells in distribution between T1DM and normal samples. Correlation of the hub genes and immune cells was analyzed by Spearman, and gene-GO-BP and gene-pathway interaction networks were constructed by Cytoscape plug-in ClueGO. Receiver operating characteristic (ROC) curves were used to assess diagnostic value of genes in T1DM. Results The 50 immune-related DEGs were obtained between the T1DM and normal samples. Then, the 50 immune-related DEGs were further screened to obtain the 5 hub genes. CIBERSORT analysis revealed that the distribution of plasma cells, resting mast cells, resting NK cells and neutrophils had significant difference between T1DM and normal samples. Natural cytotoxicity triggering receptor 3 (NCR3) was significantly related to the activated NK cells, M0 macrophages, monocytes, resting NK cells, and resting memory CD4+ T cells. Moreover, tumor necrosis factor (TNF) was significantly associated with naive B cell and naive CD4+ T cell. NCR3 [Area under curve (AUC) = 0.918] possessed a higher accuracy than TNF (AUC = 0.763) in diagnosis of T1DM. Conclusions The immune-related genes (NCR3 and TNF) and immune cells (NK cells) may play a vital regulatory role in the occurrence and development of T1DM, which possibly provide new ideas and potential targets for the immunotherapy of diabetes mellitus (DM).

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