Elsevier

Molecular Metabolism

Volume 53, November 2021, 101291
Molecular Metabolism

Original Article
Pioneer factor Foxa2 enables ligand-dependent activation of type II nuclear receptors FXR and LXRα

https://doi.org/10.1016/j.molmet.2021.101291Get rights and content
Under a Creative Commons license
open access

Highlights

  • Foxa2 opens chromatin for FXR and LXRα binding during acute ligand activation.

  • Ligand-dependent activation of FXR & LXR-dependent gene expression requires Foxa2.

  • Foxa2 interacts with FXR and LXRα in a ligand-dependent manner.

  • Foxa2 restricts binding of competing receptor PPARα to ensure proper ligand-dependent activation of FXR and LXRα.

Abstract

Objective

Type II nuclear hormone receptors, including farnesoid X receptors (FXR), liver X receptors (LXR), and peroxisome proliferator-activated receptors (PPAR), which serve as drug targets for metabolic diseases, are permanently positioned in the nucleus and thought to be bound to DNA regardless of the ligand status. However, recent genome-wide location analysis showed that LXRα and PPARα binding in the liver is largely ligand-dependent. We hypothesized that pioneer factor Foxa2 evicts nucleosomes to enable ligand-dependent binding of type II nuclear receptors and performed genome-wide studies to test this hypothesis.

Methods

ATAC-Seq was used to profile chromatin accessibility; ChIP-Seq was performed to assess transcription factors (Foxa2, FXR, LXRα, and PPARα) binding; and RNA-Seq analysis determined differentially expressed genes in wildtype and Foxa2 mutants treated with a ligand (GW4064 for FXR, GW3965, and T09 for LXRα).

Results

We reveal that chromatin accessibility, FXR binding, LXRα occupancy, and ligand-responsive activation of gene expression by FXR and LXRα require Foxa2. Unexpectedly, Foxa2 occupancy is drastically increased when either receptor, FXR or LXRα, is bound by an agonist. In addition, co-immunoprecipitation experiments demonstrate that Foxa2 interacts with either receptor in a ligand-dependent manner, suggesting that Foxa2 and the receptor, bind DNA as an interdependent complex during ligand activation. Furthermore, PPARα binding is induced in Foxa2 mutants treated with FXR and LXR ligands, leading to the activation of PPARα targets.

Conclusions

Our model requires pioneering activity for ligand activation that challenges the existing ligand-independent binding mechanism. We also demonstrate that Foxa2 is required to achieve activation of the proper receptor – one that binds the added ligand – by repressing the activity of a competing receptor.

Keywords

Lipid metabolism
Liver
Nuclear receptor
Pioneer factor
Foxa2
FXR
LXR

Cited by (0)

1

Jessica Kain and Xiaolong Wei contributed equally to this work.