Abstract
BackgroundThe liver X receptors (LXRs) are oxysterol sensing nuclear receptors with multiple effects on metabolism and immune cells. However, the complete genome-wide cistrome of LXR in cells of human origin has not yet been provided.ResultsWe performed ChIP-seq in phorbol myristate acetate-differentiated THP-1 cells (macrophage-type) after stimulation with the potent synthetic LXR ligand T0901317 (T09). Microarray gene expression analysis was performed in the same cellular model. We identified 1357 genome-wide LXR locations (FDR < 1%), of which 526 were observed after T09 treatment. De novo analysis of LXR binding sequences identified a DR4-type element as the major motif. On mRNA level T09 up-regulated 1258 genes and repressed 455 genes. Our results show that LXR actions are focused on 112 genomic regions that contain up to 11 T09 target genes per region under the control of highly stringent LXR binding sites with individual constellations for each region. We could confirm that LXR controls lipid metabolism and transport and observed a strong association with apoptosis-related functions.ConclusionsThis first report on genome-wide binding of LXR in a human cell line provides new insights into the transcriptional network of LXR and its target genes with their link to physiological processes, such as apoptosis.The gene expression microarray and sequence data have been submitted collectively to the NCBI Gene Expression Omnibus http://www.ncbi.nlm.nih.gov/geo under accession number GSE28319.
Highlights
The liver X receptors (LXRs) are oxysterol sensing nuclear receptors with multiple effects on metabolism and immune cells
The LXR antibody was successfully used in regular chromatin immunoprecipitation (ChIP) assays [20,21] and applied in a very recent LXR ChIP-seq study in mouse liver [19]
LXRa is not recognized in LXRa-/- mice, LXRb is not recognized in LXRb-/- mice and both LXR bands disappear in the LXRab-/- mice
Summary
The liver X receptors (LXRs) are oxysterol sensing nuclear receptors with multiple effects on metabolism and immune cells. High expression levels of LXRa in metabolic active tissues fit with the central role of the receptor in lipid metabolism, while LXRb is more ubiquitously expressed [4] Both LXRs are found in various cells of the immune system such as macrophages, dendritic cells and lymphocytes, which suggests an important function in the innate and adaptive immune response [5,6,7]. LXRs bind to DNA as a heterodimer with the nuclear receptor retinoid X receptor (RXR) on direct repeats (DRs) of (A/G)GGTCA core binding motifs with four intervening nucleotides (DR4) [14] These DR4type response elements (REs) have been identified in the regulatory regions of a number of primary LXR target genes [15,16,17]. Motifs for the transcription factors PU. and AP-1 were co-enriched [18]
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