Chromatin conformation changes for activation of FXR require pioneer factor Foxa2

Summary: The farnesoid X receptor (FXR) is a nuclear receptor essential for bile acid metabolism and liver homeostasis, but its role in shaping 3D genome architecture is unknown. Here, we investigate how pharmacological activation of FXR influences chromatin organization in mouse liver using FXR HiChIP, comparing FXR agonist (GW4064) treatment to vehicle controls in both wild-type and Foxa2 knockout mice. As we have shown previously with Foxa2-bound interactions (Foxa2 HiChIP), pharmacological activation of FXR induced widespread changes in genome architecture, including increased chromatin looping, topological domain reorganization, and active/inactive compartment switching in FXR-bound interactions (FXR HiChIP). FXR anchored few chromatin loops, while pioneer factor Foxa2 is associated with many. Loss of Foxa2 reduced overall interaction frequency, though compartment switching still occurred in response to FXR activation. Functional analysis of significant interactions linked FXR-induced chromatin remodeling to metabolic and detoxification pathways. In Foxa2 knockout mice, FXR activation was associated with signatures of liver stress and compensatory signaling. Our findings indicate that FXR activation remodels genome architecture to drive transcriptional changes, and that Foxa2 is required to maintain the chromatin framework that supports this regulatory activity.