Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPAR gamma

Transrepression is widely utilized to negatively regulate gene expression, but the mechanisms by which different nuclear receptors effect gene- and signal-specific transrepression programs remain poorly understood. Here, we report the identification of alternative SUMOylation-dependent mechanisms that enable PPARγ and LXRs to negatively regulate overlapping but distinct subsets of proinflammatory genes. Ligand-dependent conjugation of SUMO2/3 to LXRs or SUMO1 to PPARγ targets them to promoters of TLR target genes, where they prevent the signal-dependent removal of NCoR corepressor complexes required for transcriptional activation. SUMO1-PPARγ and SUMO2/3-LXRs inhibit distinct NCoR clearance mechanisms, allowing promoter- and TLR-specific patterns of repression. Mutational analysis and studies of naturally occurring oxysterol ligands indicate that the transactivation and SUMOylation-dependent transrepression activities of LXRs can be independently regulated. These studies define parallel but functionally distinct pathways that are utilized by PPARγ and LXRs to differentially regulate complex programs of gene expression that control immunity and homeostasis.