Enhancers serve as distal regulators of gene expression, but insights into the precise mechanisms of enhancer chromatin modifications are still lacking. In this recent review, Calo and Wysocka summarized various enhancer-associated modifications and propose how these modifications regulate enhancer activity during development.
Here are some of the key topics discussed:
The Enhancer Chromatin Landscape
Enhancers can exist in several epigenetic states, which facilitate their access by transcription factors (TFs). Active enhancers are associated with H3.3/H2A.Z histone variants that create nucleosomal hypermobility to facilitate TF binding. H3K4me1 and H3K27ac are the predominant histone modifications found at nucleosomes around enhancer elements.
H3K4me1 also characterizes “primed” enhancers prior to activation, which are also associated with pioneer TFs that directly bind nucleosomal DNA and induce chromatin remodeling events to allow TF binding. And as if that weren’t enough, a subset of ‘‘poised’’ enhancers exists in ESCs, marked by H3K27me3 and associated with PRC2 methyltransferase complexes. These enhancers are bound by TFs and coactivators and communicate with their target
H3K4me1’s “Window of Opportunity”
Instead of being tightly linked to enhancer activity, H3K4me1 is thought to provide a ‘‘window of opportunity’’ for the enhancer activation by modulating nucleosomal mobility through the H2A.Z-containing nucleosomes, resulting in more dynamic chromatin structure, facilitating TF accessibility.
DNA Methylation at Enhancers
Genome-wide DNA methylation is inversely proportional to the active enhancer histone marker enrichment, confirming that DNA methylation interferes with TF binding. But what role does DNA methylation play at shaping the enhancer landscape? Two possible scenarios are that it displaces TFs from their cognate sites or inversely, that TFs drive hypomethylation whereas DNA methylation only fills the sites vacated at enhancers by TFs. Recent evidence supports the latter idea.
This really is a great review and free as well, so check out all the details at:
Modification of Enhancer Chromatin: What, How, and Why?
Eliezer Calo and Joanna Wysocka
Molecular Cell, Volume 49, Issue 5, 825-837, 7 March 2013