Identification of an Enhancer That Controls Up-regulation of Fibronectin during Differentiation of Embryonic Stem Cells into Extraembryonic Endoderm

Shirai, Tetsu; Miyagi, Satoru; Horiuchi, Daisuke; Okuda-Katayanagi, Tomoko; Nishimoto, Masazumi; Muramatsu, Masami; Sakamoto, Yoshio; Nagata, Michio; Hagiwara, Koichi; Okuda, Akihiko

doi:10.1074/jbc.m410731200

Cited by 23 publications

(21 citation statements)

References 34 publications

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“…This Sox17 heterozygous mutant on a B6 background therefore provides a clinically relevant experimental model for congenital biliary atresia and embryonic hepatitis elicited secondarily by malformations of extrahepatic bile duct. It is well known that SOXF factors (including SOX17) are involved in the expression of the fibronectin 1 (Fn1) (Shirai et al, 2005) and laminin, alpha 1 (Lama1) (Niimi et al, 2004) genes encoding constituents of the basement membrane. Moreover, previous studies have demonstrated that SOX17 functions as a transcriptional regulator in the basal lamina formation of the extra-embryonic endoderm (Shimoda et al, 2007) and parietal endoderm (Artus et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Sox17 haploinsufficiency results in perinatal biliary atresia and hepatitis in C57BL/6 background mice

et al. 2013

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SUMMARYCongenital biliary atresia is an incurable disease of newborn infants, of unknown genetic causes, that results in congenital deformation of the gallbladder and biliary duct system. Here, we show that during mouse organogenesis, insufficient SOX17 expression in the gallbladder and bile duct epithelia results in congenital biliary atresia and subsequent acute 'embryonic hepatitis', leading to perinatal death in ~95% of the Sox17 heterozygote neonates in C57BL/6 (B6) background mice. During gallbladder and bile duct development, Sox17 was expressed at the distal edge of the gallbladder primordium. In the Sox17 +/-B6 embryos, gallbladder epithelia were hypoplastic, and some were detached from the luminal wall, leading to bile duct stenosis or atresia. The shredding of the gallbladder epithelia is probably caused by cell-autonomous defects in proliferation and maintenance of the Sox17 +/-gallbladder/bile duct epithelia. Our results suggest that Sox17 plays a dosage-dependent function in the morphogenesis and maturation of gallbladder and bile duct epithelia during the late-organogenic stages, highlighting a novel entry point to the understanding of the etiology and pathogenesis of human congenital biliary atresia.

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Section: Discussionmentioning

confidence: 99%

Sox17 haploinsufficiency results in perinatal biliary atresia and hepatitis in C57BL/6 background mice

et al. 2013

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“…Intronic cis-elements, such as enhancers or repressors, have been reported for various genes [31][32][33][34][35][36]. However, only a few studies have reported polymorphisms in the intron region of genes that determine susceptibility to complex disease traits that might function as an enhancer or repressor regulating the expression level of the gene in pathology, including rs243480 in intron 3 of the Cullin1 (CUL1) gene significantly associated with rheumatoid arthritis [37], rs909253 in intron 1 of the LTA gene and rs7291467 in intron 1 of the LGALS2 gene associated with myocardial infarction [38,39].…”

Section: Discussionmentioning

confidence: 99%

A functional intronic variant in the tyrosine hydroxylase (TH) gene confers risk of essential hypertension in the Northern Chinese Han population

Wang

et al. 2008

Clinical Science

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The TH (tyrosine hydroxylase) gene encodes the rate-limiting enzyme of catecholamine biosynthesis, and is involved in the pathogenesis of hypertension, but the relationship of its variants with hypertension has not been extensively studied. We designed a case-controlled study consisting of 503 HT (hypertensive) individuals and 490 NT (normotensive) individuals matched by region, age and gender to systematically investigate the association between the TH gene and hypertension. Based on the HapMap and dbSNP (where SNP is single nucleotide polymorphism) data, four SNPs, rs6356 A>G, rs6357 G>A, rs2070762 T>C and rs1800033 A>G in the TH gene were selected for genotyping. Rs1800033 was not polymorphic in our study population. No significant differences were observed for distributions of rs6356 and rs6357 between the HT and NT groups. However, both the genotype and allele frequencies of rs2070762 showed significant differences between cases and controls (P<0.001 and P=0.005 respectively). In haplotype analysis, a total of eight haplotypes were observed in the entire population and the overall frequency distributions differed significantly between the HT and NT groups. Specifically, haplotype A-A-C (rs6356-rs6357-rs2070762) occurred only in the HT group and A-G-C occurred more commonly in HT subjects than in NT subjects (P=0.003 and P=0.013 respectively). Compared with the most common haplotype A-G-T, the adjusted OR (odds ratio) was 1.83 [95% CI (confidence interval), 1.20-2.79; P=0.0049] for haplotype G-G-C and 20 (P<0.0001) for the haplotype A-A-C. Functional analysis showed that the C allele of rs2070762 functioned as an enhancer in the absence of binding by unidentified transcriptional repressor(s). These results provide evidence for an association of the functional intronic rs2070762 with essential hypertension.

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“…Consistent with a role for FN in determining cell phenotype, increased FN expression is associated with differentiation of embryonic stem cells (Shirai et al, 2005). Increased FN deposition contributes to a number of pathological conditions, including hepatic (Kershenobich Stalnikowitz and Weissbrod, 2003) and pulmonary fibrosis (Crouch, 1990;Hetzel et al, 2005), and diabetic nephropathy, retinopathy, and macroangiopathy (Andresen et al, 1996;Hohenadel and van der Woude, 2004).…”

Section: Introductionmentioning

confidence: 94%

Mislocalized Scaffolding by the Na-H Exchanger NHE1 Dominantly Inhibits Fibronectin Production and TGF-β Activation

Karydis

Jiménez-Vidal

Denker

et al. 2009

MBoC

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Secretion and assembly of the extracellular matrix protein fibronectin regulates a number of normal cell and tissue functions and is dysregulated in disease states such as fibrosis, diabetes, and cancer. We found that mislocalized scaffolding by the plasma membrane Na-H exchanger NHE1 suppresses fibronectin expression, secretion, and assembly. In fibroblasts, wild-type NHE1 localizes to the distal margin of membrane protrusions or lamellipodia but a mutant NHE1-KRA2 lacking binding sites for PI(4,5)P2 and the ERM proteins ezrin, radixin, and moesin is mislocalized and found uniformly along the plasma membrane. Although NHE1 regulates intracellular pH homeostasis, fibronectin production is not regulated by changes in intracellular pH, nor is it attenuated in NHE1-deficient cells, indicating fibronectin expression is independent of NHE1 activity. However, fibronectin production is nearly absent in cells expressing NHE1-KRA2 because scaffolding by NHE1 is mislocalized. Additionally, secretion of active but not latent TGF-beta is reduced and exogenous TGF-beta restores fibronectin secretion and assembly. Our data indicate that scaffolding by NHE1-KRA2 dominantly suppresses fibronectin synthesis and TGF-beta activation, and they suggest that NHE1-KRA2 can be used for obtaining a mechanistic understanding of how fibronectin production is regulated and speculatively for therapeutic control of dysregulated production in pathological conditions.

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Identification of an Enhancer That Controls Up-regulation of Fibronectin during Differentiation of Embryonic Stem Cells into Extraembryonic Endoderm

Cited by 23 publications

References 34 publications

Sox17 haploinsufficiency results in perinatal biliary atresia and hepatitis in C57BL/6 background mice

Sox17 haploinsufficiency results in perinatal biliary atresia and hepatitis in C57BL/6 background mice

A functional intronic variant in the tyrosine hydroxylase (TH) gene confers risk of essential hypertension in the Northern Chinese Han population

Mislocalized Scaffolding by the Na-H Exchanger NHE1 Dominantly Inhibits Fibronectin Production and TGF-β Activation

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