The role of hepatocyte nuclear factor 4α in regulating mouse hepatic anticoagulation and fibrinolysis gene transcript levels

Safdar, Huma; Inoue, Yusuke; Puijvelde, Gijs H van; Reitsma, Pieter H.; Vlijmen, Bart J.M. van

doi:10.1111/j.1538-7836.2010.04080.x

Cited by 4 publications

(7 citation statements)

References 16 publications

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“…Among these, HNF4A is the main transcriptional regulator in hepatocytes and regulates multiple coagulation genes (34)(35)(36)(37)(38). Other validated regulators of this community include EPB41L4B, which promotes cellular adhesion, migration and motility in vitro and is reported to play a role in wound healing (39), (40) .…”

Section: Antigen Presentation and Blood Coagulation Are Robust Commun...mentioning

confidence: 99%

Identifying key multifunctional components shared by critical cancer and normal liver pathways via sparseGMM

Bakr

Brennan

Mukherjee

et al. 2022

Preprint

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Despite the abundance of multi-modal data, suitable statistical models that can improve our understanding of diseases with genetic underpinnings are challenging to develop. Here we present SparseGMM, a novel statistical approach for gene regulatory network discovery. SparseGMM uniquely uses latent variable modeling with sparsity constraints regulators to learn gaussian mixtures from multi-omic data. By combining co-expression patterns with a Bayesian framework, sparseGMM quantitatively measures confidence in regulators and uncertainty in target gene assignment by computing gene entropy. We apply SparseGMM to liver cancer and normal liver tissue data and evaluate the discovered gene modules in an independent scRNA-seq dataset. sparseGMM identifies PROCR as a regulator of angiogenesis, and PDCD1LG2 and HNF4A as regulators of immune response and blood coagulation in cancer, respectively. Additionally, we show that more genes have significantly higher entropy in cancer compared to normal liver; among high entropy genes are key multifunctional components shared by critical pathways, such as p53 and estrogen signaling.Software availabilityThe software is available at https://hub.docker.com/r/shaimaabakr/sparse_gmmOne-sentence summaryA novel statistical approach for gene regulatory network discovery recovers modules and corresponding regulators of diverse normal liver functions, important liver cancer processes, as well as shared biology between liver cancer and normal tissue.

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Section: Antigen Presentation and Blood Coagulation Are Robust Commun...mentioning

confidence: 99%

Identifying key multifunctional components shared by critical cancer and normal liver pathways via sparseGMM

Bakr

Brennan

Mukherjee

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…They are able to regulate both platelet activation and protein involved in the regulation of hemostatic process including AT ( Figure 3). 52,53 Interestingly, miRNAs play an important role also in the regulation of gene expression during the pathogenesis of acute respiratory distress syndrome (ARDS). 54 Indeed, previous studies showed that plasma miRNAs levels are different between pulmonary and extrapulmonary ARDS patients.…”

Section: Predictive Value Of Circulating Mirnas: Potential Epigeneticmentioning

confidence: 99%

A narrative review of antithrombin use during veno-venous extracorporeal membrane oxygenation in adults: rationale, current use, effects on anticoagulation, and outcomes

et al. 2020

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Background: During extracorporeal membrane oxygenation, the large contact surface between the blood and the extracorporeal circuit causes a continuous activation of coagulation and inflammation. Unfractionated heparin, a glycosaminoglycan that must bind to antithrombin as a cofactor, is currently the standard anticoagulant adopted during extracorporeal membrane oxygenation. Antithrombin, beyond being a potent natural anticoagulant, acts in the cross-talk between coagulation and inflammatory system through anticoagulation and coagulation-independent effects. Objectives: In this review, we describe, in the adult setting of veno-venous extracorporeal membrane oxygenation, the pathophysiological rationale for antithrombin use, the current practice of administration, and the effects of antithrombin on anticoagulation, bleeding, and outcomes. Data sources: Studies on adults (18 years or older) on veno-venous extracorporeal membrane oxygenation published from 1995 to 2018 in order to evaluate the use of antithrombin. Results: In adults on veno-venous extracorporeal membrane oxygenation, antithrombin supplementation has a highly pathophysiological rationale since coagulation factor consumption, systemic inflammatory response syndrome, and endothelial activation are triggered by extracorporeal membrane oxygenation. Eleven articles are focused on the topic but among the authors there is no consensus on the threshold for supplementation (ranging from 70% to 80%) as well as on the dose (rarely standardized) and time of administration (bolus vs continuous infusion). Consistently, antithrombin is considered able to achieve better anticoagulation targets in or not in the presence of heparin resistance. The impact of antithrombin administration on bleeding still shows contrasting results. Conclusion: Antithrombin use in veno-venous extracorporeal membrane oxygenation should be investigated on the threshold for supplementation, dose, and time of administration.

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“…Hnf4a disruption affected expression of factor (F) F5 , F9 , F11 , F12 , F13b , protein C inhibitor ( Serpina5 ), protein Z ( Proz ), α2-antiplasmin ( Serpinf2 ), protein Z inhibitor ( Serpina10 ), and heparin Cofactor II ( Serpind1 ), whereas no effects were observed for F2 , F7 , F8 , F10 , protein S ( Pros1 ) and antithrombin ( Serpinc1 ) [14], [15]. For C/EBPα, studies on the relevance to coagulation are limited.…”

Section: Introductionmentioning

confidence: 97%

“…The in vivo importance of HNF4α in regulating hepatic transcription of coagulation genes described in studies using hepatocyte-specific HNF4α knockout mice [14], [15]. Hnf4a disruption affected expression of factor (F) F5 , F9 , F11 , F12 , F13b , protein C inhibitor ( Serpina5 ), protein Z ( Proz ), α2-antiplasmin ( Serpinf2 ), protein Z inhibitor ( Serpina10 ), and heparin Cofactor II ( Serpind1 ), whereas no effects were observed for F2 , F7 , F8 , F10 , protein S ( Pros1 ) and antithrombin ( Serpinc1 ) [14], [15].…”

Section: Introductionmentioning

confidence: 99%

“…Hence, the current observations regarding the role of HNF4α and C/EBPα in regulating coagulation gene transcription obtained in adult mice lacking HNF4α and C/EBPα from birth on (Cre recombinase under control of the albumin promoter) [25], following Cre supplied by means of adenovirus [26] or the MX1-Cre transgene [27] may be in part secondary to changes in liver physiology and changes in expression of other hepatic transcription factors. This may, explain the unexpected transcriptional increase of numerous hepatically expressed genes including the coagulation gene Serpind1 and absence of effects for the in vitro identified targets F2 , F7 , F8 , F10 , Pros1 and Serpinc1 in livers from mice lacking HNF4α from birth [14], [15].…”

Section: Introductionmentioning

confidence: 99%

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Modulation of Mouse Coagulation Gene Transcription following Acute In Vivo Delivery of Synthetic Small Interfering RNAs Targeting HNF4α and C/EBPα

et al. 2012

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Hepatocyte nuclear factor 4α (HNF4α) and CCAAT/enhancer-binding protein α (C/EBPα) are important for the transcriptional control of coagulation factors. To determine in vivo the direct role of HNF4α and C/EBPα in control of genes encoding coagulation factors, a synthetic small interfering (si)RNA approach was used that enabled strong reduction of mouse hepatic HNF4α and C/EBPα under conditions that minimized target-related secondary effects. For both HNF4α and C/EBPα, intravenous injection of specific synthetic siRNAs (siHNF4α and siC/EBPα) resulted in more than 75% reduction in their liver transcript and protein levels 2 days post-injection. For siHNF4α, this coincided with marked and significantly reduced transcript levels of the coagulation genes Hrg, Proz, Serpina5, F11, F12, F13b, Serpinf2, F5, and F9 (in order of magnitude of effect) as compared to levels in control siRNA injected animals. Significant decreases in HNF4α target gene mRNA levels were also observed at 5 days post-siRNA injection, despite a limited level of HNF4α knockdown at this time point. Compared to HNF4α, C/EBPα knockdown had a modest impact on genes encoding coagulation factors. A strong reduction in C/EBPα transcript and protein levels resulted in significantly affected transcript levels of the control genes Pck1 and Fasn and a modest downregulation for coagulation genes Fba, Fbg and F5. F5 and F11 were the sole coagulation genes that were significantly affected upon prolonged (5 day) C/EBPα knockdown. We conclude that in the mouse, HNF4α has a direct and essential regulatory role for multiple hepatic coagulation genes, while a role for C/EBPα is more restricted. In addition, this study demonstrates that synthetic siRNA provides a simple and fast means for determining liver transcription factor involvement in vivo.

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The role of hepatocyte nuclear factor 4α in regulating mouse hepatic anticoagulation and fibrinolysis gene transcript levels

Cited by 4 publications

References 16 publications

Identifying key multifunctional components shared by critical cancer and normal liver pathways via sparseGMM

Identifying key multifunctional components shared by critical cancer and normal liver pathways via sparseGMM

A narrative review of antithrombin use during veno-venous extracorporeal membrane oxygenation in adults: rationale, current use, effects on anticoagulation, and outcomes

Modulation of Mouse Coagulation Gene Transcription following Acute In Vivo Delivery of Synthetic Small Interfering RNAs Targeting HNF4α and C/EBPα

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