LXRs participate in the fasting response by assisting C/EBPβ binding to enhancers and promoting the fasting transcriptional program [ChIP-Seq LXR]

ABSTRACT: Upon fasting, a group of transcription factors (TFs) activate an extensive transcriptional program in the liver to alter hepatocyte metabolism and cope with fasting. This is achieved by TF-mediated activation of enhancers which become more accessible and lead to gene induction. Liver X receptors (LXRα and LXRβ) are important TFs that participate in fed transcriptional programs but their role in fasting is unclear. Here, we examined the effect of LXR deletion on the transcriptional and chromatin programs activated in fasted and fed states. We profiled the liver’s transcriptome and genome-wide chromatin accessibility in both single knockout of each LXR isoform as well as double knockout. We found that LXR deletion impairs fasting-induced genes and fasting-activated enhancers. Profiling the genome-wide profile of LXRα by ChIP-seq showed it directly binds enhancers activated by it. Surprisingly, we found that LXRs assist the binding of CCAAT/enhancer binding protein beta (C/EBPβ) to enhancers during fasting. C/EBPβ is a key TF regulating the fasting response and its binding was profoundly perturbed in the lack of LXRs across the genome. The cooperation between LXRs and C/EBPβ promoted fasting-dependent gene induction. These findings unravel a role for LXRs in the fasting response whereby LXRs bind and activate enhancers, assist C/EBPβ binding and promote gene induction. This shows the complex cooperation of TFs in regulating gene expression to maintain homeostasis during fasting and places LXRs as novel regulators of the fasting response.

ORGANISM(S): Mus musculus

PROVIDER: GSE305784 | GEO | 2026/09/21

REPOSITORIES: GEO