Involvement of Liver X Receptor Alpha in Histone Modifications Across the Target Fatty Acid Synthase Gene

The liver X receptor alpha (LXR alpha), a member of the nuclear receptor superfamily, has been shown to regulate the expression of the fatty acid synthase (FAS) gene through direct interaction with the FAS promoter. However, its regulation of gene expression is not completely understood. Histone modifications and chromatin remodeling are closely linked to transcriptional activation of genes. In the present study, we examined the effect of LXR alpha activation or silencing on histone modifications (i.e., acetylation, methylation, and phosphorylation) across the FAS gene, with the aim to investigate whether LXR alpha could regulate its target gene expression at the epigenetic level. The addition of LXR agonist T0901317 or ectopic expression of LXR alpha stimulated the FAS transcription, which was coupled with increased levels of histones H3 and H4 acetylation and H3 phosphorylation and methylation at the LXR response element (LXRE). LXR ligation or overexpression induced distinct histone modification patterns at the distal region 2,272 bp upstream from the transcription start site (TSS) and TSS of the FAS gene. Moreover, RNA interference-mediated downregulation of LXR alpha impaired the histone acetylation and methylation but not phosphorylation on the FAS gene. In conclusion, we provide evidence that LXR alpha ligation-mediated transcriptional activation of the FAS gene is associated with LXR alpha-dependent histone acetylation and methylation rather than phosphorylation on this target gene.