Figure 4. Interplay between DNA methylation status, transcription factor binding and histone modification in the patterning of enhancers.

(A) Three types of GRE have been described. Pre-programmed DHSs constitute the majority of GR occupancy upon hormone induction and are highly enriched for CGIs [(CGI) n]. The presence of cell-specific DHSs is correlated with DNA hypomethylation (open red stick). De novo binding sites are located in regions with low CpG density. Binding of GR at these sites can lead to DNA demethylation by unknown mechanisms (depicted by the binding of the unknown blue factor to GR). The third type of GRE is associated with binding sites for AP1. Recruitment of AP1 is necessary to potentiate chromatin accessibility and subsequent binding of GR. Accessible chromatin is denoted by the H3.3/H2A.Z-containing nucleosomes (light grey), whereas stable and inaccessible chromatin is denoted by H3/ H2A-containing nucleosomes (dark grey). (B) Many lineage-specific genes, located in regions with low density of CGIs, have inactive enhancers. During differentiation, binding of transcription factor PU.1 to HTF recognition sites initiates nucleosome remodelling and H3K4me1 modifications. This pre-patterning event allows recruitment of additional specific TFs and co-activators (p300) to these enhancers. In ESCs, active Oct4 enhancers, marked by H3K4me1/2 and H2K27ac histone modifications, are occupied by LSD1–NuRD complexes. The histone demethylase activity of LSD1 is inhibited, probably by the high level of Oct4 and p300. During differentiation, the decrease in Oct4 binding and loss of p300 allow LSD1 to demethylate H3K4me1 (red arrow), thereby decommissioning the active enhancer. AP1, activator protein 1; CGI, CpG island; DHS, DNase I hypersensitive site; ESC, embryonic stem cell; GR, glucocorticoid receptor; GRE, GR enhancer element; HTF, haematopoietic transcription factor; LSD1, lysine-specific demethylase 1; NuRD, nucleosome remodelling and histone deacetylase; TF, transcription factor.