Common and Differential Transcriptional Actions of Nuclear Receptors LXR and LXRβ in 1 macrophages 2

25 The liver X receptors, LXRα and LXRβ, are oxysterol-activated transcription factors that coordinately 26 regulate gene expression important for cholesterol and fatty acid metabolism. In addition to their roles in 27 lipid metabolism, LXRs participate in the transcriptional regulation of macrophage activation and are 28 considered potent regulators of inflammation. LXR receptors are highly similar and, despite notable 29 exceptions, most of their reported functions are substantially overlapping. However, their individual 30 genomic distribution and transcriptional capacities have not been characterized. Here we report a 31 macrophage cellular model expressing equivalent levels of tagged LXRs. ChIP-seq data analysis 32 revealed that LXRα and LXRβ occupy both overlapping and exclusive genomic regulatory sites of target 33 genes and also control the transcription of a receptor-exclusive set of genes. Analysis of genomic 34 H3K27 acetylation and mRNA transcriptional changes in response to synthetic agonist or antagonist 35 treatments revealed a putative mode of pharmacological-independent regulation of transcription. 36 Integration of microarray and sequencing data enabled the description of three possible mechanisms of 37 LXR transcriptional activation. Together, these results contribute to our understanding of the common 38 and differential genomic actions of LXRs and their impact on biological processes in macrophages. 39 on Jauary 3, 2019 by gest hp://m c.asm .rg/ D ow nladed fom