Cooperativity in gene expression is an important feature of many regulatory networks. Described using the Hill function, the most common example is a transcription factor (TF) that when bound to its target regulatory site, increases the rate of binding of other transcription factors (usually through TF-TF dimerization).

There are numerous example of TF dimerization-based cooperativity in the literature. However, I am trying to find examples of positive transcriptional cooperativity that involve mechanisms other than TF dimerization. In the dimer model, an unbound TF binds to its cognate promoter (containing multiple enhancers) with a certain affinity. With the first TF bound, another identical TF now has increased affinity for its target - binding to the enhancer and binding (dimerization) to the first TF. The expression profile is sigmoidal (near binary) and represents sharp on/off switching in activity.

Although peer-reviewed articles experimentally or theoretically characterizing alternative mechanisms are preferred, I'm also interested in user hypotheses and discussions that are more speculative. Specifically, I'm interested in positive cooperativity that occurs without feedback from the regulated genes.

One potential mechanism could involve a DNA-binding TF consisting of a transcriptional activator domain and a chromatin remodeling or DNA methylation domain. When the TF binds it not only activates transcription but remodels local chromatin. If the remodeling increases affinity for the next TF, they act cooperatively (and positively). Perhaps something similar to this has already been described.

  • $\begingroup$ What proteins do you think about? Transcription enhancers which are not involved directly in transcription but enhance it? $\endgroup$ – Chris Jul 20 '14 at 20:16
  • $\begingroup$ Yes, transcription enhancers, not the core machinery. $\endgroup$ – boloyao Jul 20 '14 at 20:40
  • $\begingroup$ A similar mechanism to the one I proposed in the last paragraph above, but without the chromatin remodeling domain, does appear to result in cooperativity. pnas.org/content/107/52/22534.full $\endgroup$ – boloyao Jul 20 '14 at 23:10

Positive co-operativity without feedback from the downstream genes:

I guess Polycomb/Trithorax complexes will fit this criterion nicely.

Polycomb group (PcG) represses Hox and other differentiation related genes (such as neurogenin) while Trithorax (TrxG) group promotes their expression. They are not like usual transcription factors that bind to promoters and recruit/exclude RNA-polymerase; they bind at regions called Polycomb Response Elements/Trithorax Response Elements and mediate epigenetic regulation of nearby genes by histone modifications (primarily methylation).

PcG froms two main complexes PRC1 (Polycomb Repressive Complex-1) and PRC2. Different components of the complex have different molecular functions. For e.g SuZ has a Zinc finger domain and can bind to DNA/RNA, Ezh has histone methyltransferase activity etc.

This is an old review but is still quite informative.

  • $\begingroup$ Can you explain or propose (or reference to) the underlying mechanism for polycomb/trithorax cooperativity? Thanks. $\endgroup$ – boloyao Jul 21 '14 at 16:22
  • $\begingroup$ @nbogard Edited the answer.. $\endgroup$ – WYSIWYG Jul 22 '14 at 11:27
  • $\begingroup$ The Polycomb/Trithorax system looks like it does exhibit cooperative activity. Thanks for the reference. I found this one also: nature.com/nrm/journal/v15/n5/full/nrm3789.html Specifically, the last section and fig. 7 where the authors propose that Polycomb/Trithorax Response Elements, found in target enhancers, promote bistability in target expression. Thanks! $\endgroup$ – boloyao Jul 22 '14 at 14:50

Interesting question. I think I have two examples for you which might be interesting. The first is the co-regulation of the microphthalmia-associated transcription factor (MITF) in pigmentation by SOX10 and PGC1a/b. See this paper:

The second is about the regulation of brown fat tissue by PGC1a and IRF4 which seem to interact in these cells. See this paper:

In both cases a transcription factor (SOX10 or IRF4) interacts with the co-activator PGC1 proteins to regulate gene expression. If the co-activator is missing, the expression is at least downregulated. These activations are not so atypical or rare but are occurring quite often. If you have problems in getting these articles, let me know.

  • $\begingroup$ Thanks, @Chris but I could not find an example of measured cooperativity in either of the two studies. I've edited my question to better define what I mean by 'cooperativity'. $\endgroup$ – boloyao Jul 20 '14 at 23:02
  • $\begingroup$ In the first paper SOX10 interacts with the PGCs. The knockdown of the PGCs leads to reduced pigmentation. The same is true for the knockdown of the PGCs in the pigment cell of the mice, which leads to much lighter pigmentation. In the second paper the interaction happens between IRF4 and PGC1a. If one of the partners is not present, the regulation in the fat tissue is not working. They also present data on from co-ips on the interaction of both proteins. $\endgroup$ – Chris Jul 21 '14 at 8:54
  • $\begingroup$ I do see that the activity described in these papers requires binding between the different factors, but I do not see where they measured cooperativity. I think there is some confusion about what cooperativity means. I'm specifically referring to cooperativity of biochemical binding that results in a non-linear response. en.wikipedia.org/wiki/… $\endgroup$ – boloyao Jul 21 '14 at 16:44

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