MatInspector and beyond: promoter analysis based on transcription factor binding sites

Cartharius, Kerstin; Frech, Kornelie; Grote, Korbinian; Klocke, Bernward; Haltmeier, Manuela; Klingenhoff, Andreas; Frisch, Matthias; Bayerlein, M.; Werner, Thomas

doi:10.1093/bioinformatics/bti473

Cited by 1,786 publications

(1,488 citation statements)

References 44 publications

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“…Recently, carbohydrate responsive element binding protein (ChREBP) was identified as a major glucoseresponsive transcription factor in liver cells; its consensus DNA binding site, however, consists of two E-boxes separated by 5 bp [46]. Using MatInspector (matrix similarity > 0.82) [47], we found such a potential binding site within 2 kb of the proximal USF1 and USF2 but not of the HL promoter region. Moreover, fatty acids decrease expression of glucose-responsive gene through decrease of ChREBP activity [48], whereas fatty acids increased HL [19,20] and nuclear USF expression (D. van Deursen and A. J. M. Verhoeven, unpublished observations) in HepG2 cells.…”

Section: Discussionmentioning

confidence: 92%

Glucose increases hepatic lipase expression in HepG2 liver cells through upregulation of upstream stimulatory factors 1 and 2

Deursen¹,

Jansen²,

Verhoeven³

2008

Diabetologia

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Aims/hypothesis Elevated hepatic lipase (HL, also known as LIPC) expression is a key factor in the development of the atherogenic lipid profile in type 2 diabetes and insulin resistance. Recently, genetic screens revealed a possible association of type 2 diabetes and familial combined hyperlipidaemia with the USF1 gene. Therefore, we investigated the role of upstream stimulatory factors (USFs) in the regulation of HL. Methods Levels of USF1, USF2 and HL were measured in HepG2 cells cultured in normal-or high-glucose medium (4.5 and 22.5 mmol/l, respectively) and in livers of streptozotocin-treated rats.Results Nuclear extracts of cells cultured in high glucose contained 2.5±0.5-fold more USF1 and 1.4±0.2-fold more USF2 protein than cells cultured in normal glucose (mean± SD, n=3). This coincided with higher DNA binding of nuclear proteins to the USF consensus DNA binding site. Secretion of HL (2.9±0.5-fold), abundance of HL mRNA (1.5±0.2-fold) and HL (-685/+13) promoter activity (1.8± 0.3-fold) increased in parallel. In chromatin immunoprecipitation assays, the proximal HL promoter region was immunoprecipitated with anti-USF1 and anti-USF2 antibodies. Co-transfection with USF1 or USF2 cDNA stimulated HL promoter activity 6-to 16-fold. USF and glucose responsiveness were significantly reduced by removal of the −310E-box from the HL promoter. Silencing of the USF1 gene by RNA interference reduced glucose responsiveness of the HL (−685/+13) promoter region by 50%. The hyperglycaemia in streptozotocin-treated rats was associated with similar increases in USF abundance in rat liver nuclei, but not with increased binding of USF to the rat Hl promoter region. Conclusions/interpretation Glucose increases HL expression in HepG2 cells via elevation of USF1 and USF2. This mechanism may contribute to the development of the dyslipidaemia that is typical of type 2 diabetes.

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Section: Discussionmentioning

confidence: 92%

Glucose increases hepatic lipase expression in HepG2 liver cells through upregulation of upstream stimulatory factors 1 and 2

Deursen¹,

Jansen²,

Verhoeven³

2008

Diabetologia

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“…In the human GADD45a promoter, two sets of Oct and NF-Y sites contribute to its activation by TSA (Hirose et al, 2003). However, the human GADD45b proximal promoter contains NF-Y sites but no Oct site, as predicted by MatInspector analysis (Cartharius et al, 2005). In consequence, although the three GADD45 genes are induced by TSA, the molecular mechanism underlying this induction may be different in the GADD45b gene, as compared to the GADD45a and GADD45g genes.…”

Section: Discussionmentioning

confidence: 94%

“…A search for putative transcription factor binding sites using MatInspector (Cartharius et al, 2005) revealed the presence in the À112 to À54 region of potential Oct (ATTTGCAT), and NF-Y (CCAAT) binding sites. Site-directed mutagenesis was used to generate mutated versions of the À818 construct devoid of the Oct (Octm) and NF-Y (NFYm) sites, individually or combined.…”

Section: Resultsmentioning

confidence: 99%

The histone deacetylase inhibitor trichostatin A induces GADD45γ expression via Oct and NF-Y binding sites

2007

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The GADD45c protein is a potential tumor suppressor whose expression is reduced in several tumors. However, very little is known about the regulation of its expression. We have determined that the most relevant region of its promoter lies between nucleotides À112 and À54, relative to the transcription start site. Putative Oct and NF-Y elements were found in this region and factors belonging to these families interacted with these elements in vitro and with the promoter in vivo. Mutation of these elements reduced the basal activity of the promoter, suggesting that both sites are essential for basal expression. These factors interact with chromatin modifying proteins and we found that histone deacetylase 1 or silencing mediator for retinoid and thyroid hormone receptor overexpression reduced the basal activity of the promoter. In contrast, forced expression of the histone acetylase protein PCAF or cell treatment with the HDAC inhibitor trichostatin A increased GADD45c mRNA levels and induced GADD45c promoter activity through its Oct and NF-Y elements. Moreover, ectopic expression of a dominantnegative version of NF-YA strongly inhibited trichostatin A-induced activation of the promoter. Our data strongly suggest that inhibition of deacetylase activity could potentially be used for treatment of tumors where GADD45c expression is reduced.

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“…Potential transcription factor binding sites were identified using MatInspector V6.2 (Genomatix) [15]. Settings for identification of potential transcription factor binding sites were 1.0 for core similarity and >0.85 for core matrix similarity.…”

Section: Identification Of Potential Transcription Factor Binding Sitesmentioning

confidence: 99%

Characterisation of the differentially regulated trout protein 1 (DRTP1) gene in rainbow trout (Oncorhynchus mykiss)

Talbot

Smith

Cairns

2009

Fish & Shellfish Immunology

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MatInspector and beyond: promoter analysis based on transcription factor binding sites

Cited by 1,786 publications

References 44 publications

Glucose increases hepatic lipase expression in HepG2 liver cells through upregulation of upstream stimulatory factors 1 and 2

Glucose increases hepatic lipase expression in HepG2 liver cells through upregulation of upstream stimulatory factors 1 and 2

The histone deacetylase inhibitor trichostatin A induces GADD45γ expression via Oct and NF-Y binding sites

Characterisation of the differentially regulated trout protein 1 (DRTP1) gene in rainbow trout (Oncorhynchus mykiss)

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