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Review
. 2012 Apr 10;13(5):423-30.
doi: 10.1038/embor.2012.52.

Enhancers: emerging roles in cell fate specification

Chin-Tong Ong  1 , Victor G Corces
Affiliations
Review

Enhancers: emerging roles in cell fate specification

Chin-Tong Ong et al. EMBO Rep. .

Abstract

Enhancers are regulatory DNA elements that dictate the spatial and temporal patterns of gene expression during development. Recent evidence suggests that the distinct chromatin features of enhancer regions provide the permissive landscape required for the differential access of diverse signalling molecules that drive cell-specific gene expression programmes. The epigenetic patterning of enhancers occurs before cell fate decisions, suggesting that the epigenetic information required for subsequent differentiation processes is embedded within the enhancer element. Lineage studies indicate that the patterning of enhancers might be regulated by the intricate interplay between DNA methylation status, the binding of specific transcription factors to enhancers and existing histone modifications. In this review, we present insights into the mechanisms of enhancer function, which might ultimately facilitate cell reprogramming strategies for use in regenerative medicine.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. Enhancer function correlates with distinct histone modification patterns in different cell types.
Many enhancers are characterized by the presence of H3K4me1/2, H3.3/H2A.Z and the absence of an H3K4me3 mark. (A) In human ESCs, enhancers of actively transcribed genes are marked with H3K27ac. However, enhancers associated with poised genes contain (B) H3K27me3 in human ESCs or (C) H3K9me1 and H3K27me1 in human haematopoietic stem cells. (D) In Drosophila mesodermal cells, enhancers of actively transcribed genes are marked with H3K27ac and H3K79me3. Dark grey nucleosomes contain canonical histones. Light grey nucleosomes are highly dynamic and contain histone variants. Pink nucleosomes contain modified histones that are associated with many enhancers. ESC, embryonic stem cell; SC, stem cell.
Figure 2
Figure 2. Context-dependent transcriptional output is regulated by cell-specific epigenetic features at enhancers.
(A) The presence of distinct H3K4me2-marked enhancers allows differential binding of FoxA1, which in turn recruits either ER or AR to turn on specific transcriptional programmes. (B) Enhancers of different genes are associated with distinct epigenetic marks in ESCs. Enhancers of inactive lineage-specific genes are located in regions with low CGIs and are associated with binding sites for lineage-specific transcription factors. PU.1 might be required for the deposition of the active H3K4me2 mark at these enhancers. Enhancers of poised developmental genes and active housekeeping genes contain H3K4me2 and H3K4me2/3, respectively. Both types of enhancer are located in regions with high CGI [(CGI)n]. (C) The distribution of DMRs is correlated with the presence of active H3K4me2/3 marks at distal regulatory elements in various types of T cells. Methylated and unmethylated CpG sites are denoted by filled and open red sticks, respectively. AR, androgen receptor; CGI, CpG island; DMR, differentially methylated region; ER, oestrogen receptor; ESC, embryonic stem cell; HTF, haematopoietic transcription factor.
Figure 3
Figure 3. The deposition of specific histone modifications at enhancers is regulated by different nuclear factors.
(A) In Xenopus embryos, Geminin recruitment of the Polycomb-group protein Ezh2 is necessary to restrain mesodermal and endodermal lineage commitment by maintaining the repressive H3K27me3 mark at enhancers. (B) During development of the ectoderm, Geminin promotes neural fate acquisition of mouse ESCs by maintaining chromatin of lineage-specific genes in an accessible (H3.3/H2A.Z-containing nucleosomes) and hyperacetylated state (pink-nucleosomes). (C) During liver development, the binding of the BMP signalling molecule SMAD4 at enhancers recruits p300, which in turn deposits H3K27ac marks and leads to the activation of hepatic genes. ac, acetylation; BMP, bone morphogenetic protein; ESC, embryonic stem cell; Gem, Geminin; me, methylation.
Figure 4
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.
None
Chin-Tong Ong & Victor G Corces
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