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Friday, February 09, 2024

Open and closed chromatin domains (and epigenetics)

Gene expression in eukaryotes is influenced by the state of chromatin. Tightly packed nucleosomes inhibit the binding of transcription factors and RNA polymerase so that genes in these regions are "repressed." From time to time these regions loosen up a bit allowing access to transcription complexes and subsequent transcription.

The tightly packed regions are known as closed domains and the accessible regions are open domains. Some authors add an intermediate domain called a permissive domain. This model of eukaryotic gene expression has been around for 50 years and the important mechanisms controlling the switch were worked out in the 1980s. I found a recent review that covers this issue in the context of epigenetics and the image below comes from that paper (Klemm et al., 2019).

The important mechanisms are histone modifications and demethylation. Various modifications of the histones in nucleosomes will disfavor tight packing and open up the chromatin domain. The methylation of DNA favors the closed domain so demethylation is associated with open chromatin and transcription. These two events are the main focus of epigenetics but there's a lot of confusion about the term [What the heck is epigenetics?].

Many people think that histone modifications and demethylations are ways of controlling gene expression in a way that's independent of DNA sequence. That's why they make such a big fuss about epigenetics. But none of these people can explain how histone modification enzymes and demethylation enzymes recognize a gene that needs to be expressed. That's because they are confused about correlations and cause. The best way to look at this is from the perspective of transcription factors (TF). A TF binds to the appropriate sequence and this interaction recruits histone modification enzymes and demethylation enzymes that remodel a chromatin domain to facilitate transcription.

The main features of epigenetics are just an epiphenomenon associated with transcription factor binding. Epigenetics does not require a rethinking of genes or gene expression and it does not overthrow modern evolutionary theory.

This model is Ptashne's recruitment model (Ptashne, 2013). The Klemm et al. review discusses ways that transcription factors can activate new genes found in closed domains and they conclude that TF's bind when the closed domains are temporarily open.

As chromatin accessibility is differentially regulated across the genome, TFs necessarily play a central organizing role in this process because other components of the remodelling machinery largely do not provide DNA sequence specificity....

Arguably the most elementary and parsimonious model for accessibility remodelling proposes that TFs displace nucleosomes through passive competition for DNA binding. In this mass action model, TFs gain access to histone-bound DNA by exploiting short periods of DNA accessibility during nucleosome turnover events. Local accessibility increases as the concentration of the histone-competing TF increases, providing opportunity for other TFs and cofactors to stabilize the accessible state. This mechanism is considered passive because it does not involve a direct interaction between TFs and nucleosomes; however, it is important to note that active chromatin remodellers modulate nucleosome turnover rates and are often involved in establishing a suitably permissive landscape for TF binding.

The dynamic "breathing" of heterochromatin (closed domain) means that TFs will often bind to spurious sites that become exposed from time to time. Techniques that map open domains, such as DNase I hypersensitivity, will detect these spurious sites and lead to the false conclusion that the genome is full of unknown genes.

Klemm, S.L., Shipony, Z. and Greenleaf, W.J. (2019) Chromatin accessibility and the regulatory epigenome. Nature Reviews Genetics 20:207-220. [doi: 10.1038/s41576-018-0089-8]

Ptashne, M. (2013) Epigenetics: core misconcept. Proceedings of the National Academy of Sciences 110:7101-7103. [doi: 10.1073/pnas.1305399110



Mehrshad said...

so , whats your real definition of epigentics? I am a fan of you Professor and I read your recent book... And also your blog posts about epigenetics... But I didn't understand what's your preference about preference about Epigenetics

Stephen Bunnell said...

There has also been some good work on the pioneer transcription factors commonly associated with the initial opening of chromatin domains during lineage transitions. Most were notable in that they were prone to binding one side of the DNA, possibly accessible while histone-bound, rather than using extended clamps and helices that wrap more fully around the central helical axis.

Stephen Bunnell said...

But yes, fully agree that epigenetics is an emergent property of sequence specific transcription factors, and of other factors encoded in DNA. It ‘complicates’ how information encoded in DNA is translated into action, but there is (damn near to) no evidence for the persistent inheritance of stable epigentic modifications on an evolutionary timescale…

Larry Moran said...

@Mehrshad: I don't have a preferred definition of epigenetics. I use 'regulation of gene expression' when I want to talk about that stuff. I think we should ban the word 'epigenetics' because it serves no useful purpose other than to confuse people.