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. 2021 Jul 8;53:101291. doi: 10.1016/j.molmet.2021.101291

Figure 7.

Figure 7

Foxa2 is required to enable ligand-dependent activation of the proper nuclear receptor. (A) We hypothesized that to enable ligand-dependent activation of the proper nuclear receptor, binding of a competing receptor is repressed in wildtype conditions and activated in the absence of Foxa2. (B) Venn diagrams showing PPARα binding is induced by FXR and LXR agonists in Foxa2 mutants (GW4064: 1,979 regions WT, 2,667 KO; GW3965: 110 regions WT, 2,508 regions KO; T09 313 regions WT, 1813 KO; PeakSeq, FDR < 5%, q-value < 0.07 vs. Input control). (C) Scanning motif analysis identified DR-1 elements bound by PPAR receptors, consensus sites for nuclear receptor half-site, and forkhead motif as highly enriched in regions bound by PPARα in Foxa2-deficient livers treated with FXR and LXR ligands. (D) Sites bound by PPARα during ligand activation in Foxa2 mutants overlap with regions occupied by FXR or LXR in wild-type mice in a ligand-independent manner (GW4064: 1149/2667; GW3975: 667/2508; T09: 516/1813). Heatmaps of PPARα and corresponding nuclear receptor (FXR or LXR) ChIP-Seq signal at sites bound by PPARα in Foxa2 mutants (and not in wildtype controls) treated with a ligand (GW4064 left panel, GW3965 middle panel, T09 right panel).