Mutation in the factor VII hepatocyte nuclear factor 4α-binding site contributes to factor VII deficiency

Zheng, X. Long; Kudaravalli, Rama; Russell, Theresa T.; DiMichele, Donna; Gibb, Constance; Russell, Janice; Margaritis, Paris; Pollak, Eleanor S.

doi:10.1097/mbc.0b013e3283497699

Cited by 6 publications

(9 citation statements)

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“…For example, Mutations leading to Factor VII deficiency and severe bleeding disorders occur in a promoter region harboring a CRM shared in all five species ( Figure 8—figure supplement 1A ). Several mutations (including SNP variant rs561241) within a conserved HNF4A motif have been shown to perturb F7 transcription leading to hemophilia ( Zheng et al, 2011 ). A critical highly conserved CRM localizes to the F9 promoter ( Figure 8—figure supplement 1B ).…”

Section: Resultsmentioning

confidence: 99%

Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways

Ballester

Medina-Rivera

Schmidt

et al. 2014

eLife

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As exome sequencing gives way to genome sequencing, the need to interpret the function of regulatory DNA becomes increasingly important. To test whether evolutionary conservation of cis-regulatory modules (CRMs) gives insight into human gene regulation, we determined transcription factor (TF) binding locations of four liver-essential TFs in liver tissue from human, macaque, mouse, rat, and dog. Approximately, two thirds of the TF-bound regions fell into CRMs. Less than half of the human CRMs were found as a CRM in the orthologous region of a second species. Shared CRMs were associated with liver pathways and disease loci identified by genome-wide association studies. Recurrent rare human disease causing mutations at the promoters of several blood coagulation and lipid metabolism genes were also identified within CRMs shared in multiple species. This suggests that multi-species analyses of experimentally determined combinatorial TF binding will help identify genomic regions critical for tissue-specific gene control.DOI: http://dx.doi.org/10.7554/eLife.02626.001

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Section: Resultsmentioning

confidence: 99%

Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways

Ballester

Medina-Rivera

Schmidt

et al. 2014

eLife

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“…Nuclear HNF4A is a crucial transcription factor during embryonic liver development and hepatocyte differentiation [59]. Available literature shows that HNF4A is the major liver-specific transcription factor that modulates the expression of nearly 42% of the genes expressed in hepatocytes, involved in glucose, fatty acid metabolism, synthesis of blood coagulation factor VII, enzymes involved in hepatic detoxification, and hepatic differentiation [60,61,62,63,64,65]. Our data is supported by studies showing that mRNA and protein expression levels of HNF4A decreased severely patients with cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

“…Our study also provides an explanation why HNF4A targeted protein expression is decreased in cirrhosis due to severe hepatic stress response. Studies have shown that decreased expression of HNF4A is also correlate with bleeding disorder due to decreased expression of the blood coagulation factor VII [64,65].…”

Section: Discussionmentioning

confidence: 99%

Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A-miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression

Aydın

Kurt

Song

et al. 2019

Cancers

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Hepatitis C virus (HCV) infection compromises the natural defense mechanisms of the liver leading to a progressive end stage disease such as cirrhosis and hepatocellular carcinoma (HCC). The hepatic stress response generated due to viral replication in the endoplasmic reticulum (ER) undergoes a stepwise transition from adaptive to pro-survival signaling to improve host cell survival and liver disease progression. The minute details of hepatic pro-survival unfolded protein response (UPR) signaling that contribute to HCC development in cirrhosis are unknown. This study shows that the UPR sensor, the protein kinase RNA-like ER kinase (PERK), mediates the pro-survival signaling through nuclear factor erythroid 2-related factor 2 (NRF2)-mediated signal transducer and activator of transcription 3 (STAT3) activation in a persistent HCV infection model of Huh-7.5 liver cells. The NRF2-mediated STAT3 activation in persistently infected HCV cell culture model resulted in the decreased expression of hepatocyte nuclear factor 4 alpha (HNF4A), a major liver-specific transcription factor. The stress-induced inhibition of HNF4A expression resulted in a significant reduction of liver-specific microRNA-122 (miR-122) transcription. It was found that the reversal of hepatic adaptive pro-survival signaling and restoration of miR-122 level was more efficient by interferon (IFN)-based antiviral treatment than direct-acting antivirals (DAAs). To test whether miR-122 levels could be utilized as a biomarker of hepatic adaptive stress response in HCV infection, serum miR-122 level was measured among healthy controls, and chronic HCV patients with or without cirrhosis. Our data show that serum miR-122 expression level remained undetectable in most of the patients with cirrhosis (stage IV fibrosis), suggesting that the pro-survival UPR signaling increases the risk of HCC through STAT3-mediated suppression of miR-122. In conclusion, our data indicate that hepatic pro-survival UPR signaling suppresses the liver-specific HNF4A and its downstream target miR-122 in cirrhosis. These results provide an explanation as to why cirrhosis is a risk factor for the development of HCC in chronic HCV infection.

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“…Patients homozygous for deleterious promoter mutations reducing transcription of the FVII gene (F7) [17], [18], [19], [20], [21], although rare, have been diagnosed following severe bleeding episodes that usually first occur during infancy. The phenotype of the F7 knockout mouse is reminiscent of that of patients with severe FVII deficiency.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of the Coagulation Factor VII Gene during Glucose Deprivation Is Mediated by Activating Transcription Factor 4

2012

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BackgroundConstitutive production of blood coagulation proteins by hepatocytes is necessary for hemostasis. Stressful conditions trigger adaptive cellular responses and delay processing of most proteins, potentially affecting plasma levels of proteins secreted exclusively by hepatocytes. We examined the effect of glucose deprivation on expression of coagulation proteins by the human hepatoma cell line, HepG2.Methodology/Principal FindingsExpression of coagulation factor VII, which is required for initiation of blood coagulation, was elevated by glucose deprivation, while expression of other coagulation proteins decreased. Realtime PCR and ELISA demonstrated that the relative percentage expression +/− SD of steady-state F7 mRNA and secreted factor VII antigen were significantly increased (from 100+/−15% to 188+/−27% and 100+/−8.8% to 176.3+/−17.3% respectively, p<0.001) at 24 hr of treatment. The integrated stress response was induced, as indicated by upregulation of transcription factor ATF4 and of additional stress-responsive genes. Small interfering RNAs directed against ATF4 potently reduced basal F7 expression, and prevented F7 upregulation by glucose deprivation. The response of the endogenous F7 gene was replicated in reporter gene assays, which further indicated that ATF4 effects were mediated via interaction with an amino acid response element in the F7 promoter.Conclusions/SignificanceOur data indicated that glucose deprivation enhanced F7 expression in a mechanism reliant on prior ATF4 upregulation primarily due to increased transcription from the ATF4 gene. Of five coagulation protein genes examined, only F7 was upregulated, suggesting that its functions may be important in a systemic response to glucose deprivation stress.

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Mutation in the factor VII hepatocyte nuclear factor 4α-binding site contributes to factor VII deficiency

Cited by 6 publications

References 0 publications

Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways

Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways

Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A-miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression

Upregulation of the Coagulation Factor VII Gene during Glucose Deprivation Is Mediated by Activating Transcription Factor 4

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