HNF4A is required to specify glucocorticoid action in the liver

Abstract

The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR are highly dependent on cell type and environmental context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver-specificity of GR action. In normal mouse liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Lost sites are characterised by HNF4 motifs and weak GRE motifs. Gained sites are characterised by strong GRE motifs, and typically show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is further demonstrated by evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.

Enhancer RNA Expression in Response to Glucocorticoid Treatment in Murine Macrophages

“…Differential motif enrichment of the myeloid-specific eGBS subset over the hepatic eGBS subset identified the lineage factor SPI1/Pu.1 [77] and the inflammatory transcription factors AP-1 and NF-κB as enriched in macrophages (Figure 2D), validating previous analyses [78,79]. Vice versa, the hepatocyte lineage factors HNF4 and FoxA cooccurred at liver-specific eGBSs (Figure 2D) [80,81]. Among the shared GBSs, we identified motifs for AP-1 as well as the C2H2 zinc finger containing krüppel-like factor (KLF) family as commonly enriched over either the macrophage-specific or liver-specific sequencing reads (Figure 2D).…”