General Enhancer Questions (Methylation Patterns, ect.)

Question

I have a biological question(s) for ya'll involving enhancers.

1.) Enhancers work by being the binding sites for TFs. But how does this increase transcription? (Especially when enhancers can be extremely far away from the gene they control.)

2.) Enhancers can become methylated. When they do, does this usually prevent transcription factor binding? And if it does prevent the binding, how does this affect the role of the TF and gene expression.

EDIT: Here's what I found.

It seems that enhancers can be far away from the gene they act upon, but the binding of TF via their DNA-binding domain can cause looping of DNA to help them reach the promoter region of the gene of interest. Thus, increasing the rate of gene expression.

On the reverse, methylation can sometimes be seen to act as silencing of gene expression. So, if our enhancer region is methylated, this may prevent TF binding and the enhancer from increasing gene expression.

BONUS: Methylation in promoters can also cause silencing by preventing RNA polymerase II, and the required proteins (ect) from carrying transcription.

If anybody wants to add (or correct anything, let me know!)

Answer 1

This subject is actually both complicated and incompletely understood. For example, there is evidence that some enhancers don't result in loops at all — instead their influence travels along the chromatin to a nearby promoter.

You can think of enhancers as being staging areas where protein complexes that promote transcription are assembled. In some cases enhancers are where the RNA polymerase complex is first bound.

When loops do form, this allows the proteins at an enhancer to interact directly with the transcriptional start site.

I think you will find this 2015 review to be a helpful introduction.¹

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As for methylation (which maybe would be better as a separate question), it is generally true that methylation acts to reduce transcription factor binding and thus decreases transcription.²

However, that overall trend disguises some more complex dynamics.³

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References:

1: Pennacchio, L. A., Bickmore, W., Dean, A., Nobrega, M. A., & Bejerano, G. (2013). Enhancers: five essential questions. Nature Reviews Genetics, 14(4), 288.

2: Lea, A. J., Vockley, C. M., Johnston, R. A., Del Carpio, C. A., Barreiro, L. B., Reddy, T. E., & Tung, J. (2018). Genome-wide quantification of the effects of DNA methylation on human gene regulation. ELife, 7, e37513.

3: Sharifi-Zarchi, A., Gerovska, D., Adachi, K., Totonchi, M., Pezeshk, H., Taft, R. J., ... & Araúzo-Bravo, M. J. (2017). DNA methylation regulates discrimination of enhancers from promoters through a H3K4me1-H3K4me3 seesaw mechanism. BMC genomics, 18(1), 964.