Hepatocyte Nuclear Factor 4-Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver.
Avinash ThakurJasper C H WongEvan Y WangJeremy LottoDonghwan KimJung-Chien ChengMatthew MingayRebecca CullumVaishali MoudgilNafeel AhmedShu-Huei TsaiWei WeiColum P WalshTabea StephanMisha BilenkyBettina M FuglerudMohammad M KarimiFrank J GonzalezMartin HirstPamela A HoodlessPublished in: Hepatology (Baltimore, Md.) (2019)
Cell-fate determination is influenced by interactions between master transcription factors (TFs) and cis-regulatory elements. Hepatocyte nuclear factor 4 alpha (HNF4A), a liver-enriched TF, acts as a master controller in specification of hepatic progenitor cells by regulating a network of TFs to control onset of hepatocyte cell fate. Using analysis of genome-wide histone modifications, DNA methylation, and hydroxymethylation in mouse hepatocytes, we show that HNF4A occupies active enhancers in hepatocytes and is essential for active histone and DNA signatures, especially acetylation of lysine 27 of histone 3 (H3K27ac) and 5-hydroxymethylcytosine (5hmC). In mice lacking HNF4A protein in hepatocytes, we observed a decrease in both H3K27ac and hydroxymethylation at regions bound by HNF4A. Mechanistically, HNF4A-associated hydroxymethylation (5hmC) requires its interaction with ten-eleven translocation methylcytosine dioxygenase 3 (TET3), a protein responsible for oxidation from 5mC to 5hmC. Furthermore, HNF4A regulates TET3 expression in liver by directly binding to an enhancer region. Conclusion: In conclusion, we identified that HNF4A is required for the active epigenetic state at enhancers that amplifies transcription of genes in hepatocytes.
Keyphrases
- nuclear factor
- dna methylation
- genome wide
- cell fate
- toll like receptor
- liver injury
- transcription factor
- gene expression
- drug induced
- binding protein
- poor prognosis
- inflammatory response
- amino acid
- mass spectrometry
- single molecule
- hydrogen peroxide
- type diabetes
- immune response
- high resolution
- cell free
- long non coding rna
- metabolic syndrome
- skeletal muscle
- insulin resistance
- histone deacetylase
- adipose tissue