Abstract
The nuclear receptors liver X receptor (LXR) α and β play crucial roles in hepatic metabolism. Many genes induced in response to pharmacologic LXR agonism have been defined; however, the transcriptional consequences of loss of LXR binding to its genomic targets are less well characterized. Here, we addressed how deletion of both LXRα and LXRβ from mouse liver (LXR double knockout [DKO]) affects the transcriptional regulatory landscape by integrating changes in LXR binding, chromatin accessibility, and gene expression. Many genes involved in fatty acid metabolism showed reduced expression and chromatin accessibility at their intergenic and intronic regions in LXRDKO livers. Genes that were up-regulated with LXR deletion had increased chromatin accessibility at their promoter regions and were enriched for functions not linked to lipid metabolism. Loss of LXR binding in liver reduced the activity of a broad set of hepatic transcription factors, inferred through changes in motif accessibility. By contrast, accessibility at promoter nuclear factor Y (NF-Y)motifs was increased in the absence of LXR. Unexpectedly, we also defined a small set of LXR targets for direct ligand-dependent repression. These genes have LXR-binding sites but showed increased expression in LXRDKO liver and reduced expression in response to the LXR agonist. In summary, the binding of LXRs to the hepatic genome has broad effects on the transcriptional landscape that extend beyond its canonical function as an activator of lipid metabolic genes.
Highlights
The nuclear receptors liver X receptor (LXR) α and β play crucial roles in hepatic metabolism
Down-regulated genes associated with lipid metabolism pathways as expected and overlapped substantially with the set of direct LXR target genes annotated in publicly available ChIP-Seq datasets (SI Appendix, Fig. S2 A and B)
We assessed the implications of loss of LXR expression in mouse liver for gene expression, chromatin accessibility, and transcription factor activity
Summary
The nuclear receptors liver X receptor (LXR) α and β play crucial roles in hepatic metabolism. Loss of LXR binding in liver reduced the activity of a broad set of hepatic transcription factors, inferred through changes in motif accessibility. We defined a small set of LXR targets for direct ligand-dependent repression These genes have LXR-binding sites but showed increased expression in LXRDKO liver and reduced expression in response to the LXR agonist. The binding of LXRs to the hepatic genome has broad effects on the transcriptional landscape that extend beyond its canonical function as an activator of lipid metabolic genes. Chromatin immunoprecipitation with sequencing (ChIP-Seq) studies have defined LXRbinding sites in the hepatic genome and noted increased LXR binding to lower-affinity DNA sites in the presence of a synthetic agonist [27].
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