Chromatin occupancy of transcription factor 7-like 2 (TCF7L2) and its role in hepatic glucose metabolism

Norton, Luke; Fourcaudot, Marcel; Abdul‐Ghani, Muhammad; Winnier, Deidre; Mehta, Fabiola F.; Jenkinson, Chris; DeFronzo, Ralph A.

doi:10.1007/s00125-011-2289-z

Cited by 80 publications

(96 citation statements)

References 42 publications

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“…Recent reports have shown that mouse TCF7L2 expression is insulin-responsive [20,22] and that in insulin-resistant mice expression of the short and medium C-terminal transcripts (e.g. including T3 and T5) was reduced [21]. Our data on human liver transcript expression show that the expression of five liver TCF7L2 transcripts (T2, T4, T7, T8, T9) was increased in type 2 diabetic compared with normoglycaemic individuals.…”

Section: Discussionsupporting

confidence: 50%

“…Transcription of some genes may be directly regulated by TCF7L2 binding to their promoter and/or enhancer sequences, as has been reported for PCK1 and GYS2, while others (G6PC) have not been reported to have TCF7L2 recognition sites [21,[31][32][33]. Therefore, we analysed the role of TCF7L2 in the HNF4α-FOXO1-mediated transcriptional regulation of G6PC.…”

Section: Discussionmentioning

confidence: 87%

“…Two specific TCF7L2 isoforms interact with HNF4α protein No direct TCF7L2 binding on the G6PC promoter region was reported in ChIP binding studies [21,[31][32][33]. Therefore, we hypothesised that TCF7L2 could regulate G6PC transcription by interacting with HNF4α protein.…”

Section: Statistical Analysesmentioning

confidence: 94%

“…TCF7L2 expression is highest in pericentral hepatocytes, where gluconeogenesis is low [20]. As evidence that TCF7L2 affects liver glucose metabolism [20][21][22] is accumulating, we sought to further characterise the expression of alternative human TCF7L2 transcripts in livers of normoglycaemic and type 2 diabetes individuals genotyped for rs7903146. We also analysed expression levels of these transcripts in HepG2 cells incubated with different glucose concentrations in the presence or not of insulin, as well as the mRNA expression of 84 genes related to glucose metabolism, subsequent to downregulation of TCF7L2 by small interfering RNA (siRNA).…”

Section: Introductionmentioning

confidence: 99%

“…We also analysed expression levels of these transcripts in HepG2 cells incubated with different glucose concentrations in the presence or not of insulin, as well as the mRNA expression of 84 genes related to glucose metabolism, subsequent to downregulation of TCF7L2 by small interfering RNA (siRNA). Hepatic gluconeogenesis is tightly controlled by rate-limiting enzymes, such as glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase, which are both inhibited by a TCF7L2-dependent pathway [20][21][22]. Hepatocyte nuclear factor 4α (HNF4α) and forkhead box O1 (FOXO1) are transcriptional regulators of G6PC, which mediates regulation of gluconeogenesis in response to feeding or fasting [23].…”

Section: Introductionmentioning

confidence: 99%

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Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level

et al. 2014

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Aims/hypothesis Gene polymorphisms of TCF7L2 are associated with increased risk of type 2 diabetes and transcription factor 7-like 2 (TCF7L2) plays a role in hepatic glucose metabolism. We therefore addressed the impact of TCF7L2 isoforms on hepatocyte nuclear factor 4α (HNF4α) and the regulation of gluconeogenesis genes.Methods Liver TCF7L2 transcripts were analysed by quantitative PCR in 33 non-diabetic and 31 type 2 diabetic obese individuals genotyped for TCF7L2 rs7903146. To analyse transcriptional regulation by TCF7L2, small interfering R N A t r a n s f e c t i o n , l u c if e r a s e r e p o r t e r a n d c oimmunoprecipitation assays were performed in human hepatoma HepG2 cells. Results In livers of diabetic compared with normoglycaemic individuals, five C-terminal TCF7L2 transcripts showed increased expression. The type 2 diabetes risk allele of rs7903146 positively correlated with TCF7L2 expression in livers from normoglycaemic individuals only. In HepG2 cells, transcript and TCF7L2 protein levels were increased upon incubation in high glucose and insulin. Of the exon 13 transcripts, six were increased in a glucose doseresponsive manner. TCF7L2 transcriptionally regulated 29 genes related to glucose metabolism, including glucose-6-phosphatase. In cultured HepG2 cells, TCF7L2 did not regulate HNF4Α and FOXO1 transcription, but did affect HNF4α protein expression. The TCF7L2 isoforms T6 and T8 (without exon 13 and with exon 15/14, respectively) specifically interacted with HNF4α. Conclusions/interpretation The different levels of expression of alternative C-terminal TCF7L2 transcripts in HepG2 cells, in livers of normoglycaemic individuals carrying the rs7901346 type 2 diabetes risk allele and in livers of diabetic individuals suggest that these transcripts play a role in the pathophysiology of type 2 diabetes. We also report for the first time a protein interaction in HepG2 cells between HNF4α and the T6 and T8 isoforms of TCF7L2, which suggests a distinct role for these specific alternative transcripts.

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 87%

Section: Statistical Analysesmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level

et al. 2014

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A candidate functional SNP rs7074440 in TCF7L2 alters gene expression through C‐FOS in hepatocytes

et al. 2018

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The SNP rs7903146 at the transcription factor 7-like 2 (TCF7L2) locus is established as the strongest known genetic marker for type 2 diabetes via genome-wide association studies. However, the functional SNPs regulating TCF7L2 expression remain unclear. Here, we show that the SNP rs7074440 is a candidate functional SNP highly linked with rs7903146. A reporter plasmid with rs7074440 normal allele sequence exhibited 15-fold higher luciferase activity compared with risk allele sequence in hepatocytes, demonstrating a strong enhancer activity at rs7074440. Additionally, we identified C-FOS as an activator binding to the rs7074440 enhancer using a TFEL genome-wide screen method. Consistently, knockdown of C-FOS significantly reduced TCF7L2 expression in hepatocytes. Collectively, a novel enhancer regulating TCF7L2 expression was revealed through searching for functional SNPs.

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Finding a Needle in a Genomic Haystack

Bhambhani¹,

Cadigan²

2014

WNT Signaling in Development and Disease

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Chromatin occupancy of transcription factor 7-like 2 (TCF7L2) and its role in hepatic glucose metabolism

Cited by 80 publications

References 42 publications

Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level

Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level

A candidate functional SNP rs7074440 in TCF7L2 alters gene expression through C‐FOS in hepatocytes

Finding a Needle in a Genomic Haystack

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