The selection and function of cell type-specific enhancers - PubMed (original) (raw)
Review
The selection and function of cell type-specific enhancers
Sven Heinz et al. Nat Rev Mol Cell Biol. 2015 Mar.
Abstract
The human body contains several hundred cell types, all of which share the same genome. In metazoans, much of the regulatory code that drives cell type-specific gene expression is located in distal elements called enhancers. Although mammalian genomes contain millions of potential enhancers, only a small subset of them is active in a given cell type. Cell type-specific enhancer selection involves the binding of lineage-determining transcription factors that prime enhancers. Signal-dependent transcription factors bind to primed enhancers, which enables these broadly expressed factors to regulate gene expression in a cell type-specific manner. The expression of genes that specify cell type identity and function is associated with densely spaced clusters of active enhancers known as super-enhancers. The functions of enhancers and super-enhancers are influenced by, and affect, higher-order genomic organization.
Figures
Figure 1
The anatomies of poised and active enhancers. The characteristic features of poised and active enhancers are shown, including the binding of lineage-determining transcription factors (LDTFs) and collaborating transcription factors (CTFs) to closely spaced recognition motifs (blue and green sites, respectively) on the DNA. The binding of these factors in concert with nucleosome remodeling complexes (NRCs) initiates nucleosome displacement to form narrow nucleosome free regions at poised enhancers (top). At poised enhancers, the redundant histone methyltransferases (HMTs) myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3) and MLL4 deposit the active H3K4me1 and H3K4me2 marks, whereas EZH2 (a component of the polycomb complex) deposits repressive H3K27me3 and histone deacetylase (HDAC)-containing complexes maintain histones in a repressed deacetylated state. Pol II is either absent or low at poised enhancers. In response to various cues, signal-dependent transcription factors (SDTFs) associate with recognition motifs in close association with LDTFs, which results in additional nucleosome displacement (bottom), as observed by widening of the DNase I-hypersensitive sites. SDTFs recruit co-activator complexes containing histone demethylase (HDM) complexes that remove H3K27me3 marks, histone acetyltransferase (HAT) that deposit H2K27ac, and the mediator complex. The transformation to elongating Pol II results in bidirectional transcription — a hallmark of active enhancers — and the generation of enhancer RNAs (eRNA), which is closely coupled to enhancer activity.
Figure 2
Cell type-specific enhancers are marked by specific epigenomic features and chromatin accessibility. Genomic features of a ~60 kb region of human chromosome 1 centered around the TAL1 gene ENCODE consortium data of DNase-I hypersensitive (DNase HS) regions and ChIP-Seq for the marks H3K4me2, H3K27me3 and H3K27ac in 7 cell lines. Enhancers known to be responsible for TAL1 transcription in endothelial cells (the −3.8 kb and +19 kb enhancers, relative to the TAL1 promoter, in HUVEC cells) and erythroid cells (the +51 kb enhancer in K562 cells) exhibit cell type-specific DNase HS, H3K4me2 and H3K27ac signals. In cell types where TAL1 is not expressed, the promoter and gene body are devoid of DNase HS and histone modifications indicative of enhancer activation (H3K4me2, H3K27ac), and exhibit variable levels of the repressive H3K27me3 mark. Shaded boxes indicate cell-restricted or cell-specific enhancers regions.
Figure 3
Cell type-specific enhancer selection and activation. A. Collaborative interactions between lineage-determining transcription factors (LDTFs) and collaborating transcription factors (CTFs) select enhancers for binding and activation by signal-dependent transcription factors (SDTFs). Prior to signal-dependent activation, such regions may be ‘poised’ enhancers or exhibit basal enhancer activity (‘pre-existing’ enhancers) that is further induced by the binding of a SDTF. The resulting transcription is cell type-specific because the enhancers are selected by the cell type-specific LDTFs. B. SDTFs can direct the selection of latent or de novo enhancers. In these cases, the SDTF functions as an essential collaborative transcription factor to LDTFs to enable concurrent binding of all factors involved. The transcriptional output is cell type-specific because of the requirement for cell type-specific LDTFs for enhancer priming.
Figure 4
Enhancer activation and function. A. Interactions between enhancers and promoters involve structural connections (orange oval) that include cohesin and the mediator complex to promote pre-initiation complex formation, initiate transcription and/or overcome Pol II pausing. A potential role of enhancer RNAs (eRNAs) could be to promote transcription by facilitating chromatin looping, possibly by mediating interactions with cohesin. Another potential role could be to mediate interactions with protein complexes required for transcriptional elongation, such as the mediator complex. LDTFs, lineage-determining transcription factors; CTFs, collaborating transcription factors; SDTFs, signal-dependent transcription factors. B. Potential roles of enhancer transcription. In activated macrophages the NF-κB proteins p50 and p65 are signal-dependent transcription factors and PU.1 is a lineage-determining transcription factor that collaboratively select de novo enhancers. The subsequent recruitment of histone acetyltransferases (HAT) results in histone acetylation, which is bound by the Brd4 component of the P-TEFb complex, allowing its Cdk9 component to phosphorylate the C-terminal domain (CTD) of Pol II. Phosphorylated CTD acts as docking sites for the MLL3 and MLL4 histone H3K4 methyltransferases. MLL3 and MLL4 are proposed to deposit H3K4me1 and H3K4me2 during successive rounds of Pol II elongation.
Figure 5
The linear and the three-dimensional organization of enhancers in the nucleus. The outer circle represents the linear coordinates of a region of human chromosome 1 surrounding the Atf3 (activating transcription factor 3) gene in C57BL/6J mouse macrophages. The locations of individual genes are indicated by gene names and purple bars. The three successive concentric inner circles depict ChIP-Seq data of, respectively, histone H3 Lys 27 acetylation (H3K27ac), the transcription factor PU.1, and the transcription repressor CCCTC-binding factor (CTCF), which is enriched at boundaries of topological domains. A region of high density of H3K27ac in the vicinity of the Atf3 gene is designated as a super-enhancer. Purple and black lines in the center of the circle indicate physical contacts involving promoters and other genomic regions, respectively, as determined by statistically significant genome-wide chromatin connectivity measurements determined by tethered conformation capture. This locus demonstrates the multitude of connections between the individual enhancers comprising the Atf3 super-enhancer, which essentially forms its own TAD, as well as the longer-range enhancer-enhancer and enhancer-promoter interactions outside of the TAD.
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