Different nuclear receptors (NR) recognize different binding sequences, thus regulating different target genes specifically. However, for each single NR, it remains a very interesting question that how it achieves the specificity in regulating each of its target genes that contain the same or very similar binding sequences. This paper exemplified how a coregulator-GPS2 is involved in mediating such specificity of LXR. LXR regulates two cholesterol transporters-ABCA1 and ABCG1—in very different ways. Before ligand binding, LXR binds to ABCA1 promoter at low level and is associated with a corepressor complex that includes GPS2; ligand binding to LXR enhances its recruitment to the promoter and leads to binding of coactivators that replace GPS2 and other corepressors. In contrast, for ABCG1 gene, in absence of ligand, no LXR or GPS2 is recruited; upon ligand stimulation, both LXR and GPS2 are recruited as well as other coactivators. In addition, GPS2 is shown to facilitate KDM-LXR interaction that results in H3K9 demethylation on ABCG1.
A few interesting points: 1. There is an interdependency between LXR and GPS2 binding to ABCG1 sites. 2. GPS2-LXR binding surface is different from LXR-coactivator binding surface, and the two are independent of each other. Unlike GPS2, coactivator binding is not required for liganded LXR binding to ABCG1. 3. ABCG1 gene contains two LXR response elements in the promoter and intronic enhancer, comparing to one in ABCA1 promoter. This should be part of the reasons why the two genes are controlled in different manner. 4. GPS2 appears to be able to associate with either corepressors or coactivators, depending on the gene context. It would be interesting to see what could happen if in some way the binding sites on ABCA1 and ABCG1 can be mixed or swapped,for instance,when ABCA1 promoter sits together with ABCG1 enhancer. Also the LRE in ABCG1 enhancer can be disrupted by mutation to see any effect.
Different nuclear receptors (NR) recognize different binding sequences, thus regulating different target genes specifically. However, for each single NR, it remains a very interesting question that how it achieves the specificity in regulating each of its target genes that contain the same or very similar binding sequences. This paper exemplified how a coregulator-GPS2 is involved in mediating such specificity of LXR. LXR regulates two cholesterol transporters-ABCA1 and ABCG1—in very different ways. Before ligand binding, LXR binds to ABCA1 promoter at low level and is associated with a corepressor complex that includes GPS2; ligand binding to LXR enhances its recruitment to the promoter and leads to binding of coactivators that replace GPS2 and other corepressors. In contrast, for ABCG1 gene, in absence of ligand, no LXR or GPS2 is recruited; upon ligand stimulation, both LXR and GPS2 are recruited as well as other coactivators. In addition, GPS2 is shown to facilitate KDM-LXR interaction that results in H3K9 demethylation on ABCG1.
ReplyDeleteA few interesting points:
1. There is an interdependency between LXR and GPS2 binding to ABCG1 sites.
2. GPS2-LXR binding surface is different from LXR-coactivator binding surface, and the two are independent of each other. Unlike GPS2, coactivator binding is not required for liganded LXR binding to ABCG1.
3. ABCG1 gene contains two LXR response elements in the promoter and intronic enhancer, comparing to one in ABCA1 promoter. This should be part of the reasons why the two genes are controlled in different manner.
4. GPS2 appears to be able to associate with either corepressors or coactivators, depending on the gene context. It would be interesting to see what could happen if in some way the binding sites on ABCA1 and ABCG1 can be mixed or swapped,for instance,when ABCA1 promoter sits together with ABCG1 enhancer. Also the LRE in ABCG1 enhancer can be disrupted by mutation to see any effect.