#73. How Enhancers May Work [Biochemistry]

 CH

Red, theory; black, fact.

Background about enhancers

Enhancers are stretches of DNA that, when activated by second messengers like cyclic AMP, enhance the activity of specific promoters in causing the transcription of certain genes, leading to the translation of these genes into protein. Enhancers are known for causing the post-translational modification of the histones associated with them. Typically, lysine side chains on histones are methylated, doubly methylated, triply methylated, or acetylated. Serines are phosphorylated. In general, phosphorylation condenses chromatin and acetylation expands and activates it for transcription. Methylation increases positive electric charge on the histones, acetylation decreases positive charge, and phosphorylation increases negative charge. The enhancers of a promoter are usually located far away from it measuring along the DNA strand, and can even be on different chromosomes ("in trans"). 

The mystery of enhancer–promoter interaction

How the distant enhancer communicates with its promoter is a big mystery. The leading theory is that the enhancer goes and sticks to the promoter, and the intervening length of DNA sticks out of the resulting complex as a loop. This is the "transcription hub" theory. 

My electrostatic theory of enhancer–promoter interaction

I propose a far different mechanism: when activated, the multiple enhancers cause modification of their associated histones that place the same electric charge on all of them, which is also of the same sign as the charge on the promoter region. Mutual electrostatic repulsion of all these regions then expands the chromatin around the promoter. This effect reduces the fraction of the time that the RNA polymerase II cannot move down the DNA strand because unrelated chromatin loops are in the way, like trees fallen across the railway tracks. (Each "tree" eventually moves away because of Brownian motion.) This could also be the mechanism of chromatin decondensation generally, which is known to be a precondition for the expression of protein-coding genes.

05-28-2022: The mutual electrostatic repulsion of enhancers does not necessarily accomplish decondensation directly, but may do so indirectly, by triggering a cascade of alternating chromatin expansions and histone modifications. Furthermore, this cascade is not necessarily deterministic. These ideas predict that raising the ionic strength in the nuclear compartment, which would tend to shield charges from each other, should inhibit gene activation. This manipulation will require genetic knockout of osmolarity regulating genes.