TAF4, a subunit of transcription factor II D, directs promoter occupancy of nuclear receptor HNF4A during post-natal hepatocyte differentiation

Alpern, Daniel; Langer, Diana; Ballester, Benoît; Gras, Stéphanie Le; Romier, Christophe; Mengus, Gabrielle; Davidson, Irwin

doi:10.7554/elife.03613

Cited by 36 publications

(42 citation statements)

References 50 publications

(62 reference statements)

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“…To determine if these changes in Octn2 and CrAT were due to direct regulation by HNF4α, we interrogated publically available ChIP-Seq data sets to determine whether HNF4α occupies their promoters (Alpern et al, 2014). HNF4α binding peaks were observed in proximity to promoters of PPARα, Cpt1b, Octn2, and CrAT (Figure 5F).…”

Section: Resultsmentioning

confidence: 99%

Global Analysis of Plasma Lipids Identifies Liver-Derived Acylcarnitines as a Fuel Source for Brown Fat Thermogenesis

et al. 2017

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Summary Cold induced thermogenesis is an energy demanding process that protects endotherms against a reduction in ambient temperature. Using non-targeted LC-MS based lipidomics, we identified elevated levels of plasma acylcarnitines in response to the cold. We found that the liver undergoes a metabolic switch to provide fuel for brown fat thermogenesis by producing acylcarnitines. Cold stimulates white adipocytes to release free fatty acids that activate the nuclear receptor HNF4α, which is required for acylcarnitine production in the liver and adaptive thermogenesis. Once in circulation, acylcarnitines are transported to brown adipose tissue, while uptake into white adipose tissue and liver is blocked. Finally, a bolus of L-carnitine or palmitoylcarnitine rescues the cold sensitivity seen with aging. Our data highlights an elegant mechanism whereby white adipose tissue provides long chain fatty acids for hepatic carnitilation to generate plasma acylcarnitines as a fuel source for peripheral tissues in mice.

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Section: Resultsmentioning

confidence: 99%

Global Analysis of Plasma Lipids Identifies Liver-Derived Acylcarnitines as a Fuel Source for Brown Fat Thermogenesis

et al. 2017

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“…Furthermore, Estrogen Receptor α (Esrra), which is known to regulate gene expression in coordination with HNF4α and PGC1A (26), was also predicted to be inhibited. TAF4, a known HNF4α cofactor which is required for HNF4α transcriptional activity (27), was also inhibited. MED1, which is essential for PPARα activity and required for survival after PH (28), was inhibited in HNF4α-KO 2 days post-PH.…”

Section: Hnf4α-ko Mice Post-phmentioning

confidence: 99%

Hepatocyte Nuclear Factor 4 alpha (HNF4α) Activation is Essential for Termination of Liver Regeneration

Huck

Gunewardena

Español–Suñer

et al. 2018

Preprint

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Hepatocyte Nuclear Factor 4 alpha (HNF4α) is critical for hepatic differentiation. Recent studies have highlighted its role in inhibition of hepatocyte proliferation and tumor suppression.However, the role of HNF4α in liver regeneration is not known. We hypothesized that hepatocytes modulate HNF4α activity when navigating between differentiated and proliferative states during liver regeneration. Western blot analysis revealed a rapid decline in nuclear and cytoplasmic HNF4α protein levels accompanied with decreased target gene expression within 1 hour after 2/3 partial hepatectomy (post-PH) in C57BL/6J mice. HNF4α protein expression did not recover to the pre-PH levels until day 3. Hepatocyte-specific deletion of HNF4α (HNF4α-KO) in mice resulted in 100% mortality post-PH despite increased proliferative marker expression throughout regeneration. Sustained loss of HNF4α target gene expression throughout regeneration indicated HNF4α-KO mice were unable to compensate for loss of HNF4α transcriptional activity. Deletion of HNF4α resulted in sustained proliferation accompanied by cmyc and cyclin D1 over expression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation-resistant HNF4α in hepatocytes did not prevent initiation of regeneration after PH. Finally, AAV8-mediated reexpression of HNF4α in hepatocytes of HNF4α-KO mice post-PH restored HNF4α protein levels, induced target gene expression and improved survival of HNF4α-KO mice post-PH. In conclusion, these data indicate that HNF4α reexpression following initial decrease is critical for hepatocytes to exit from cell cycle and resume function during the termination phase of liver regeneration. These results reveal the role of HNF4α in liver regeneration and have implications for therapy of liver failure.

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“…CLIP-GENE uses TF network to select candidate DEG genes by following edges between TF and target genes. TF network used for CLIP-GENE was constructed using normal inbred mice data that vary in strains, developmental stage, and tissues (150 samples of wild type mice RNA-seq data from 17 independent studies) [37–53]. NARROMI [54] was used for the TF network construction.…”

Section: Methodsmentioning

confidence: 99%

CLIP-GENE: a web service of the condition specific context-laid integrative analysis for gene prioritization in mouse TF knockout experiments

et al. 2016

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MotivationTranscriptome data from the gene knockout experiment in mouse is widely used to investigate functions of genes and relationship to phenotypes. When a gene is knocked out, it is important to identify which genes are affected by the knockout gene. Existing methods, including differentially expressed gene (DEG) methods, can be used for the analysis. However, existing methods require cutoff values to select candidate genes, which can produce either too many false positives or false negatives. This hurdle can be addressed either by improving the accuracy of gene selection or by providing a method to rank candidate genes effectively, or both. Prioritization of candidate genes should consider the goals or context of the knockout experiment. As of now, there are no tools designed for both selecting and prioritizing genes from the mouse knockout data. Hence, the necessity of a new tool arises.ResultsIn this study, we present CLIP-GENE, a web service that selects gene markers by utilizing differentially expressed genes, mouse transcription factor (TF) network, and single nucleotide variant information. Then, protein-protein interaction network and literature information are utilized to find genes that are relevant to the phenotypic differences. One of the novel features is to allow researchers to specify their contexts or hypotheses in a set of keywords to rank genes according to the contexts that the user specify. We believe that CLIP-GENE will be useful in characterizing functions of TFs in mouse experiments.Availability http://epigenomics.snu.ac.kr/CLIP-GENE ReviewersThis article was reviewed by Dr. Lee and Dr. Pongor.Electronic supplementary materialThe online version of this article (doi:10.1186/s13062-016-0158-x) contains supplementary material, which is available to authorized users.

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TAF4, a subunit of transcription factor II D, directs promoter occupancy of nuclear receptor HNF4A during post-natal hepatocyte differentiation

Cited by 36 publications

References 50 publications

Global Analysis of Plasma Lipids Identifies Liver-Derived Acylcarnitines as a Fuel Source for Brown Fat Thermogenesis

Global Analysis of Plasma Lipids Identifies Liver-Derived Acylcarnitines as a Fuel Source for Brown Fat Thermogenesis

Hepatocyte Nuclear Factor 4 alpha (HNF4α) Activation is Essential for Termination of Liver Regeneration

CLIP-GENE: a web service of the condition specific context-laid integrative analysis for gene prioritization in mouse TF knockout experiments

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