Enhancer States

Cited from The selection and function of cell type-specific enhancers

1. Enhancer states can broadly be classified as inactive, primed, poised or active. 
2. An inactive enhancer is essentially buried in compact chromatin and is devoid of transcription factor binding and histone modifications. 
3. Primed enhancers are characterized by closely bound sequence-specific transcription factors that establish a DNase I-hypersensitive and nucleosome-free region of open chromatin.
4. However, they may require additional cues to accomplish their function, which may include signal-dependent activation, the recruitment of additional transcription factors and the eventual recruitment of co-activators that lead to enhancer activation.
5. Poised enhancers can be defined as primed enhancers that also contain repressive epigenetic chromatin marks, a state that is most commonly found in ESCs.
6. The redundant histone methyltransferases myeloid/lymphoid or mixed-lineage leukaemia protein 3 (MLL3) and MLL4 deposit the active histone H3 lysine 4 monomethylation (H3K4me1) and H3K4me2 marks.
7. At poised enhancers, the histone-lysine N-methyltransferase EZH2 (a component of the Polycomb complex) deposits repressive H3K27me3 marks, and histone deacetylase (HDAC)-containing complexes maintain histones in a repressed, deacetylated state.
8. RNA polymerase II (Pol II) is either absent or found at low levels at poised enhancers.
9. 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, as observed by widening of the DNase I-hypersensitive sites.
10. SDTFs recruit co-activator complexes containing histone demethylase (HDM) complexes that remove H3K27me3 marks, histone acetyltransferases (HATs) that deposit H3K27 acetylation (H3K27ac) marks, and the Mediator complex (MED).
11. Primed enhancer-like regions are marked with H3K4me1 and H3K4me2 and lack histone acetylation, and enhancers marked additionally by H3K27me3, a repressive mark, are considered to be poised. 
12. Features associated with active enhancers include H3K27 acetylation (H3K27ac) and the presence of actively transcribing Pol II. 
13. Lineage-determining transcription factors (LDTF) motif composition may be one of the contributing factors to the formation of transcriptionally inactive and active genomic compartments. 
14. ChIP–seq studies of signal-dependent transcription factors (SDTFs) in different cell types found both common and cell type-specific binding sites.
15. Of note, the histone methylation signature of latent enhancers persists after the cessation of cell stimulation and is associated with more-rapid and more-diverse transcriptional responses to subsequent stimulation. These observations provide evidence that the writing of the H3K4me1 signature in enhancers provides a molecular 'memory' of prior activation.