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I have an inquiry regarding the regulation of genes via extracellular signaling.

To my knowledge, in autocrine, paracrine, and endocrine cellular communication, large protein ligands that cannot directly diffuse through the plasma membrane of the target cell(s) use surface receptors to perform their desired action on the target cell(s).

I have learned that some of these ligands activate signal transduction pathways such as the MAPK/ERK and JAK/STAT pathway and drive the expression of specific genes by utilizing transcription factors (of course, in eukaryots). A simple example of this would be the action of epinephrine (adrenaline) on hepatocytes (liver cells), where the amino acid-based hormone uses the transcription factor CREB to express the gene coding for Glycogen Phosphorylase to engage in glycogenolysis.

Here I have two questions:

  1. How does the transcription factor chemically indicate which gene to express? (Is there a gene indexing system like a computer filesystem?)

  2. How does the transcription factor locate and bind to the promoter of the gene it is trying to express?

Thank you.

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  • $\begingroup$ 1: by recognizing the promotor sequence. 2: trial and error. TFs don't have eyes nor a brain or ways to propel themselves. Somehow the answers are in the question it seems, as 2 answers 1, while 2 is basically chemistry in a way. $\endgroup$ – AliceD Aug 20 '15 at 13:49
  • $\begingroup$ @AliceD But don't most genes have similar promoter sequence patterns? How could we specify a set of transcription factors to express a specific gene? If trial and error was used, signal transduction pathways that involve gene expression would pitifully fail most of the time. $\endgroup$ – 0fb1d8 Aug 20 '15 at 13:59
  • $\begingroup$ Subquestion 2 does not have "specificity" included. As of now, it looks like you wish to know how it gets to its target. maybe refine your question a bit and perhaps the whole story on signal transduction is not really relevant? $\endgroup$ – AliceD Aug 20 '15 at 14:13
  • $\begingroup$ Most genes have a similar core promoter but varying proximal and distal promoters which contain specific TF binding sites. Signalling pathways are integrated with other signals and the status of the cell in order to correctly express genes. $\endgroup$ – canadianer Aug 20 '15 at 14:37
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This is a combination of multiple regulatory systems. Most genes are not regulated by a single factor, but by many. Moreover in eukaryotic organisms there is also epigenetic, which "inactivates" permanently certain areas of the genome by compacting these zones forming heterochromatin.

Moreover, even when we are interested in a single function a TF might have, that does not mean that it only has this function in the cell. We view it as humans, and maybe for us it is logical that a response to a high metabolite in the environment simply leads to expressing the protein that metabolizes it. However, probably it is interesting for the cell to also activate other pathways and gene networks (i.e. anabolic pathways that feed off this metabolite, compensatory pathways to mantain homeostasis...). Because that normally TFs affect more than one gene naturally.

The mechanisms of action of the TFs are multiple, but they tend to simply allow or deny the access to the adequate RNA polymerase. For more information about this check the wikipedia article on TF structure

In this image we see a typical mechanism of action, DNA bending

Different domains interact in activating a gene, enhancers which are usually long distance, promoters which tend to be in the upstream region, though they can be downstream or in the gene sequence, and epigenetic factors that change the compaction of DNA, making it inaccessible to proteins.

Just as a last thing to point out, you should acknowledge that the biological systems are far from exact and yes, a single TF might activate 200 genes, even when its main objective in that moment is to activate one, but it won't really matter as long as the those 199 activated genes express at a very low rate (for example by not having the right RNA polymerase subunit accessible, being marked as inactive by epigenetic systems or having their own inhibitors).

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  • $\begingroup$ Thank you so much!! You just clarified my understanding of gene regulation! $\endgroup$ – 0fb1d8 Aug 20 '15 at 14:38
  • $\begingroup$ I'd also like to add with respect to many text figures, that while the coactivating complex Mediator isn't necessarily required in all instances of gene regulation, it does give the transcription a level of robustness you wouldn't otherwise get without it. More on mediator here. $\endgroup$ – CKM Aug 20 '15 at 18:33

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