【百文】【文献通读】Pioneer factor Foxa2 enables ligand-dependent activation of LXRα

Jessica Kain, Xialong Wei, Andrew J Price, Claire Woods, Irina Bochkis

Type II nuclear hormone receptors, such as FXR, LXR, and PPAR, which function in glucose and lipid metabolism and serve as drug targets for metabolic diseases, are permanently positioned in the nucleus regardless of the ligand status. Ligand activation of these receptors is thought to occur by co-repressor/co-activator exchange, followed by initiation of transcription. However, recent genome-wide location analysis showed that LXR and PPAR binding in the liver is largely ligand-dependent. We hypothesized that pioneer factor Foxa2 evicts nucleosomes to enable ligand-dependent receptor binding. We show that chromatin accessibility, LXR occupancy, and LXR-dependent gene expression upon ligand activation require Foxa2. Unexpectedly, Foxa2 occupancy is drastically increased when LXR is bound by an agonist. Our results suggest that Foxa2 and LXR bind DNA as an interdependent complex during ligand activation. Our model requiring pioneering activity for ligand activation challenges the existing co-factor exchange mechanism and expands current understanding of nuclear receptor biology, suggesting that chromatin accessibility needs to be considered in design of drugs targeting nuclear receptors.

Publisher URL: http://biorxiv.org/cgi/content/short/2020.04.10.036061v1
DOI: https://doi.org/10.1101/2020.04.10.036061

背景：
type I nuclear receptors, such as ER and AR
Type II nuclear hormone receptors, such as FXR, LXR, and PPAR；

科学问题：
PTFs FOXA2与typII糖脂代谢相关核激素受体的关系。

样本：
mice; Foxa2 mutant mice (Foxa2loxP/loxP); LXRα null mice (LXRα-/-) ；

主要实验方法：
ATCA-seq; ChIP-seq; RNA-seq; WB;

结果:
ligand-responsive activation of gene expression by both FXR and LXRα is Foxa2-dependent;
Foxa2 and LXRα bind DNA as an interdependent complex during ligand activation
提出了新的model （fig5）：

1. LXRα could play the role of a co-activator without binding DNA；
2. both Foxa2 and LXRα need to be bound either in a proximal interaction；
3. in distal interaction;

讨论：
与typeI receptor 区别

ligand, nuclear receptor (来自网络)

fig1a-c

fig1d-g

fig2

fig3

fig4

fig5a

fig5b