An integrated approach for the identification of USF1-centered transcriptional regulatory networks during liver regeneration

Chen, Huan; Lu, Shan; Zhou, Jing; Bai, Zihe; Fu, Hailong; Xu, Xiaoping; Yang, Shengsheng; Jiao, Binghua; Sun, Yimin

doi:10.1016/j.bbagrm.2014.03.010

Cited by 6 publications

(6 citation statements)

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“…We have adopted the integrated approach of mRNA/OATFA/ChIP-DSL/oPOSSUM analysis to characterize the target genes and co-regulatory network of USF1 during early liver regeneration in our previous study [16]. To the best of our knowledge, it was the first report of TF activity profiling during liver regeneration.…”

Section: Discussionmentioning

confidence: 99%

“…oPOSSUM to identify TF binding sites occupancy and predict the co-regulatory relationship between TFs and targets. We have previously reported that 43 TFs were found to be active in normal liver tissues in mice via the OATFA (TF-array) platform [16], among which the binding matrix of 18 TFs were included in the present analysis. The selection of 18 TFs including HNF4 suggests that these active TFs in regenerating liver tissues (1 downregulated TF, 6 upregulated TFs and 10 active but unchanged TFs) might be involved in the transcriptional regulation of the 15 target genes.…”

Section: Identification Of Hnf4α Target Genesmentioning

confidence: 99%

“…Integration of ChIP-on-chip analysis and gene expression profiling has been reported to be an effective strategy to identify potential target genes of a specific TF and its co-regulator [16]. Firstly, we employed a ChIP-DSL analysis to identify potential target genes of HNF4α, which is a new ChIP-onchip model that offers a powerful strategy to evaluate in vivo binding profiles of a specific TF with high accuracy [17].…”

Section: Identification Of Hnf4α Target Genesmentioning

confidence: 99%

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An Integrated Approach for the Identification of HNF4α-Centered Transcriptional Regulatory Networks During Early Liver Regeneration

Jiao

Zhu

et al. 2015

Cell Physiol Biochem

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Background/Aims: Hepatocyte nuclear factor-4α (HNF4α), the liver enriched transcription factor (TF), is one of the major regulators of hepatocyte differentiation and proliferation. However, how HNF4α participate in liver regeneration after partial hepatectomy (PH) remains largely unknown. In order to identify the HNF4α-centered regulatory network, we applied an integrated analytic strategy, in which, TF array, mRNA microarray, bioinformatic analysis and ChIP-on-chip assays were integrated. Methods/Results: The TF signatures from MOUSE OATFA (TF-array) platform revealed that the activity of HNF4α was significantly reduced and 17 other TFs showed increased activity at 4 h post PH. Then the ChIP-on-chip analysis on HNF4α were combined with mRNA expression profiling to select the possible HNF4α target genes during early liver regeneration, which were then sub-grouped according to their signaling pathways. More specifically, the HNF4α target genes with the gene ontology (GO) terms of cytokine-cytokine receptor, Jak-STAT, MAPK, toll-like receptor and insulin signaling pathways were further analyzed with an advanced bioinformatics tool named oPOSSUM to identify TF binding sites occupancy and predict the co-regulatory relationship between TFs and targets. Furthermore, we identified that repressed HNF4α during the early phase of liver regeneration may contribute cooperatively to the induction of immediate early genes, such as, c-fos, c-jun and stat3. Conclusion: our data indicate that HNF4α may play an inhibitory role on the induction of specific promitogenic genes and liver regeneration initiation. The integrated approach of mRNA/OATFA/ChIP-DSL/oPOSSUM analysis may help us better characterize the target genes and co-regulatory network of HNF4α during the early stage of liver regeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Identification Of Hnf4α Target Genesmentioning

confidence: 99%

Section: Identification Of Hnf4α Target Genesmentioning

confidence: 99%

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An Integrated Approach for the Identification of HNF4α-Centered Transcriptional Regulatory Networks During Early Liver Regeneration

Jiao

Zhu

et al. 2015

Cell Physiol Biochem

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“…Indeed, recent studies have shown that shortly after PH there is a reduction in the transcriptional regulatory activity of HNF4 α in the liver of young mice. 61 , 62 Although this decrease in HNF4 α activity may be due to its physical redistribution on the genome, as occurs during liver development, 74 we observed a transient but clear downregulation of HNF4 α gene expression in the first hours post PH. This previously unrecognized response may be part of the molecular mechanisms allowing the entry of otherwise quiescent hepatocytes into the cell cycle.…”

Section: Discussionmentioning

confidence: 63%

“…HNF4 α transcriptional activity is repressed in the first hours after PH, allowing the induction of early genes mediating the onset of liver regeneration. 61 , 62 Consequently, we evaluated HNF4 α expression shortly after PH and found a transient but significant downregulation of Hnf4α expression during the normal regenerative response in young mice ( Figure 6b ). These observations suggest that Hnf4α downregulation may also contribute to the pro-regenerative activity of Fibapo in aged mice livers.…”

Section: Resultsmentioning

confidence: 97%

Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice

et al. 2017

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The liver displays a remarkable regenerative capacity triggered upon tissue injury or resection. However, liver regeneration can be overwhelmed by excessive parenchymal destruction or diminished by pre-existing conditions hampering repair. Fibroblast growth factor 19 (FGF19, rodent FGF15) is an enterokine that regulates liver bile acid and lipid metabolism, and stimulates hepatocellular protein synthesis and proliferation. FGF19/15 is also important for liver regeneration after partial hepatectomy (PH). Therefore recombinant FGF19 would be an ideal molecule to stimulate liver regeneration, but its applicability may be curtailed by its short half-life. We developed a chimaeric molecule termed Fibapo in which FGF19 is covalently coupled to apolipoprotein A-I. Fibapo retains FGF19 biological activities but has significantly increased half-life and hepatotropism. Here we evaluated the pro-regenerative activity of Fibapo in two clinically relevant models where liver regeneration may be impaired: acetaminophen (APAP) poisoning, and PH in aged mice. The only approved therapy for APAP intoxication is N-acetylcysteine (NAC) and no drugs are available to stimulate liver regeneration. We demonstrate that Fibapo reduced liver injury and boosted regeneration in APAP-intoxicated mice. Fibapo improved survival of APAP-poisoned mice when given at later time points, when NAC is ineffective. Mechanistically, Fibapo accelerated recovery of hepatic glutathione levels, potentiated cell growth-related pathways and increased functional liver mass. When Fibapo was administered to old mice prior to PH, liver regeneration was markedly increased. The exacerbated injury developing in these mice upon PH was attenuated, and the hepatic biosynthetic capacity was enhanced. Fibapo reversed metabolic and molecular alterations that impede regeneration in aged livers. It reduced liver steatosis and downregulated p21 and hepatocyte nuclear factor 4 α (Hnf4α) levels, whereas it stimulated Foxm1b gene expression. Together our findings indicate that FGF19 variants retaining the metabolic and growth-promoting effects of this enterokine may be valuable for the stimulation of liver regeneration.

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Determination of key events in mouse hepatocyte maturation at the single-cell level

et al. 2023

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An integrated approach for the identification of USF1-centered transcriptional regulatory networks during liver regeneration

Cited by 6 publications

References 46 publications

An Integrated Approach for the Identification of HNF4α-Centered Transcriptional Regulatory Networks During Early Liver Regeneration

An Integrated Approach for the Identification of HNF4α-Centered Transcriptional Regulatory Networks During Early Liver Regeneration

Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice

Determination of key events in mouse hepatocyte maturation at the single-cell level

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