scholarly journals Transactivation of the Mouse Sulfonylurea Receptor I Gene by BETA2/NeuroD

2002 ◽  
Vol 16 (5) ◽  
pp. 1097-1107 ◽  
Author(s):  
Ji-Won Kim ◽  
Victor Seghers ◽  
Jang-Hyeon Cho ◽  
Yup Kang ◽  
Soyeon Kim ◽  
...  

Abstract The sulfonylurea receptor 1 (SUR1) plays a key role in regulation of insulin secretion in pancreatic β-cells. In this study we investigated the mechanism for tissue-specific expression of the SUR1 gene. A −138/−20 fragment exhibited basal promoter activity while the −660/−20 fragment contained a regulatory element for tissue-specific expression of the mouse SUR1 gene. A pancreatic β-cell-specific transcription factor, BETA2 (β-cell E box transcription factor)/NeuroD, enhanced the promoter activity of the −660/−20 fragment in cooperation with E47. Coexpression of a dominant negative mutant of BETA2/NeuroD, BETA2(1–233), repressed the promoter activity of the −660/−20 fragment. BETA2/NeuroD bound specifically to the E3 element located at −141. The E3 sequence in a heterologous context conferred transactivation by BETA2/NeuroD in HeLa and HIT cells. Mutation of E3 eliminated the stimulatory effect of BETA2/NeuroD. Unlike BETA2/NeuroD, neurogenin 3 (ngn3) could not activate the E3 element in HeLa cells. Overexpression of ngn3 concomitantly increased expression of BETA2/NeuroD and SUR1 in HIT cells but not in HeLa cells. These results indicate that BETA2/NeuroD induces tissue-specific expression of the SUR1 gene through the E3 element. These results also suggest that E3 is specific for BETA2/NeuroD, and the stimulatory effect of ngn3 in HIT cells may require factors specifically expressed in HIT cells.


2006 ◽  
Vol 394 (3) ◽  
pp. 617-626 ◽  
Author(s):  
Bao-Liang Song ◽  
Can-Hua Wang ◽  
Xiao-Min Yao ◽  
Li Yang ◽  
Wen-Jing Zhang ◽  
...  

Humans express two ACAT (acyl-CoA:cholesterol acyltransferase) genes, ACAT1 and ACAT2. ACAT1 is ubiquitously expressed, whereas ACAT2 is primarily expressed in intestinal mucosa and plays an important role in intestinal cholesterol absorption. To investigate the molecular mechanism(s) responsible for the tissue-specific expression of ACAT2, we identified five cis-elements within the human ACAT2 promoter, four for the intestinal-specific transcription factor CDX2 (caudal type homeobox transcription factor 2), and one for the transcription factor HNF1α (hepatocyte nuclear factor 1α). Results of luciferase reporter and electrophoretic mobility shift assays show that CDX2 and HNF1α exert a synergistic effect, enhancing the ACAT2 promoter activity through binding to these cis-elements. In undifferentiated Caco-2 cells, the ACAT2 expression is increased when exogenous CDX2 and/or HNF1α are expressed by co-transfection. In differentiated Caco-2 cells, the ACAT2 expression significantly decreases when the endogenous CDX2 or HNF1α expression is suppressed by using RNAi (RNA interference) technology. The expression levels of CDX2, HNF1α, and ACAT2 are all greatly increased when the Caco-2 cells differentiate to become intestinal-like cells. These results provide a molecular mechanism for the tissue-specific expression of ACAT2 in intestine. In normal adult human liver, CDX2 expression is not detectable and the ACAT2 expression is very low. In the hepatoma cell line HepG2 the CDX2 expression is elevated, accounting for its elevated ACAT2 expression. A high percentage (seven of fourteen) of liver samples from patients affected with hepatocellular carcinoma exhibited elevated ACAT2 expression. Thus, the elevated ACAT2 expression may serve as a new biomarker for certain form(s) of hepatocellular carcinoma.



1997 ◽  
Vol 122 (1) ◽  
pp. 17-24 ◽  
Author(s):  
S. Tsuzuki ◽  
T. Kojima ◽  
A. Katsumi ◽  
T. Yamazaki ◽  
I. Sugiura ◽  
...  


1995 ◽  
Vol 311 (3) ◽  
pp. 835-843 ◽  
Author(s):  
S K Böhm ◽  
J R Gum ◽  
R H Erickson ◽  
J W Hicks ◽  
Y S Kim

The dipeptidyl peptidase IV gene encodes a plasma-membrane exopeptidase that is highly expressed in small intestine, lung and kidney. In order to better understand the mechanisms responsible for this tissue-specific expression we cloned, sequenced and functionally characterized the 5′-flanking region of the human dipeptidyl peptidase IV gene. The first 500 bases of the 5′-flanking sequence constituted an unmethylated CpG island, contained several Sp1-binding sites and lacked a consensus TATA box, all characteristics of gene promoters lacking tissue-specific expression. RNase-protection analysis using both small intestinal and Caco2 cell RNA indicated that the dipeptidyl peptidase IV transcript was initiated from no fewer than six major and 12 minor start sites. The 5′-flanking sequence also exhibited functional promoter activity in transient transfection experiments. Here, various lengths of the sequence were cloned upstream of a luciferase gene and introduced into cultured cells using lipofectin. A region located between bases -150 and -109 relative to the start of translation was found to be important for high-level promoter activity in both Caco2 and HepG2 cells. Moreover, Caco2 cells and HepG2 cells, which express high levels of dipeptidyl peptidase IV activity, exhibited much higher normalized luciferase activity after transfection than did 3T3, Jurkat or COS-7 cells, which have low enzyme levels. Sodium butyrate was found to increase both enzyme activity and normalized luciferase in HepG2 cells. Thus the dipeptidyl peptidase IV promoter possesses the ability to initiate transcription in a tissue-specific fashion in spite of having the sequence characteristics of a housekeeping gene promoter.





2020 ◽  
Author(s):  
Sruti Chandra ◽  
Kenneth C. Ehrlich ◽  
Michelle Lacey ◽  
Carl Baribault ◽  
Melanie Ehrlich

AbstractExcessive inflammatory signaling and pathological remodeling of the extracellular matrix are important contributors to cardiac fibrosis and involve major changes in gene expression. We examined the relationships between tissue-specific expression and the epigenetics of five genes involved in these pathways, NLRP3, MMP2, MMP9, CCN2/CTGF, and AGT. The proteins encoded by these genes play major fibrosis-related roles in inflammasome formation, degradation of extracellular matrix proteins and remodeling of the extracellular matrix and vasculature, autocrine regulation of fibrosis, or cell signaling. Our analyses showed that the first four of these genes had super-enhancers (unusually strong enhancer clusters) that correlate with their very high expression in monocytes, neutrophils, fibroblasts, or venous cells. Expression of the gene encoding miR-223, a micro-RNA that plays an important role in downregulating NLRP3 protein levels, is also probably driven by the super-enhancer in which it is embedded. Enhancer chromatin for all these genes was inside as well as outside the gene body. While AGT, which encodes precursors of angiotensin II, lacked a super-enhancer, its tissue-specific expression profile correlates with the tissue-specific enhancer chromatin extending into its distant silent gene neighbor (CAPN9). Tissue-specific peaks of DNA hypomethylation, open chromatin (DNaseI hypersensitivity), and transcription factor binding were detected in subregions of these super-enhancers/enhancers that are likely to be the main drivers of expression of their associated gene. We found that CCN2/CTGF is co-expressed with its far-upstream neighbor LINC01013, a noncoding RNA gene, specifically in vein endothelial cells (HUVEC) and chondrocytes. Evidence from chromatin looping profiling (Hi-C) suggests coregulation of these genes in HUVEC. Our findings indicate the importance of understanding the often-overlooked roles of enhancers and their hypomethylated, transcription factor-binding subregions in the regulation of expression of fibrosis-related genes in normal and fibrotic tissue.



1990 ◽  
Vol 4 (10) ◽  
pp. 1650-1662 ◽  
Author(s):  
M Yamamoto ◽  
L J Ko ◽  
M W Leonard ◽  
H Beug ◽  
S H Orkin ◽  
...  




2004 ◽  
Vol 101 (9) ◽  
pp. 2930-2933 ◽  
Author(s):  
T.-a. Matsuoka ◽  
I. Artner ◽  
E. Henderson ◽  
A. Means ◽  
M. Sander ◽  
...  




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