Super-enhancer
A super-enhancer, illustrated in the lower panel of the Figure, is a region of the mammalian genome comprising multiple typical enhancers that is collectively bound by an array of transcription factor proteins to drive transcription of genes involved in cell identity,[3][4][5] or of genes involved in cancer.
[5][7] Super-enhancers are also central to mediating dysregulation of signaling pathways and promoting cancer cell growth.
[25] In the nucleus of mammalian cells, almost all the DNA is wrapped around regularly spaced protein complexes, called nucleosomes (see top panel in Figure "Chromatin").
P-TEFb acts as a kinase that phosphorylates RNA polymerase II (RNAP II), which then activates (in conjunction with the Mediator complex described below) the polymerase on the promoter of a gene to initiate transcription and to continue transcription (instead of pausing).
[31] The transcription factors, bound to their sites on each enhancer within the super-enhancer, recruit the Mediator complex between each enhancer and the RNA polymerase II that will initiate transcription of the gene to be actively transcribed (see Figure at top of article that illustrates a super-enhancer).
[32] The tail modules of the Mediator complex protein sub-units interact with the activation domains of transcription factors bound at enhancers and the head and middle modules interact with the pre-initiation complex (PIC) at gene promoters.
[39][40][41][42] More recent research has suggested that these different categories of regulatory elements may represent subtypes of super-enhancer.
[4][44] As currently defined, the term “super-enhancer” was introduced by Young’s lab to describe regions identified in mouse embryonic stem cells (ESCs).
[3] These particularly large, potent enhancer regions were found to control the genes that establish the embryonic stem cell identity, including Oct-4, Sox2, Nanog, Klf4, and Esrrb.
[3][5][43][44] Three notable traits of enhancers comprising super-enhancers are their clustering in genomic proximity, their exceptional signal of transcription-regulating proteins, and their high frequency of physical interaction with each other.
[44] Super-enhancers separated by tens of megabases cluster in three-dimensions inside the nucleus of mouse embryonic stem cells.
[44] Pathways seen to regulate their target genes using super-enhancers include Wnt, TGFb, LIF, BDNF, and NOTCH.
[44][64][65][66][67] The constituent enhancers of super-enhancers physically interact with each other and their target genes over a long range sequence-wise.
This is notably the case for B-lymphocytes, the survival, the activation and the differentiation of which rely on the expression of membrane-form immunoglobulins (Ig).
[10][11][49][85] For instance, super-enhancers rely on exceptional amounts of CDK7, and, in cancer, multiple papers report the loss of expression of their target genes when cells are treated with the CDK7 inhibitor THZ1.
[10][13][14][86] Similarly, super-enhancers are enriched in the target of the JQ1 small molecule, BRD4, so treatment with JQ1 causes exceptional losses in expression for super-enhancer—associated genes.
[11] Super-enhancers have been most commonly identified by locating genomic regions that are highly enriched in ChIP-Seq signal.
ChIP-Seq experiments targeting master transcription factors and co-factors like Mediator or BRD4 have been used, but the most frequently used is H3K27ac-marked nucleosomes.
[3] The stitching distance selected to combine multiple individual enhancers into larger domains can vary.
