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First up, I am NOT asking about how to search for and match regulatory elements using a database. I'm asking about how people found what to search for and match in a genome, how they built those databases. My question is,

How did people identify regulatory proteins/nucleotide elements in the first place?

Did they first find the proteins we now call transcription factors and sigma factors, or did they tamper with the genome to find the regulatory parts and then traced them to the proteins?

Is there a book on the history of research gene regulation to recommend?

Also, I tried Googling. Every site recommended one database or the other. I would be grateful too if you could tell me what should I have searched for?

I am more interested in Prokaryotes, but answers on Eukaryotes would also be welcome.

Context: I'm a freshman doing research (yep. the experience is kinda crazy for me) and I'm interested in finding regulatory elements in Mycobacterium smegmatis and its phages.

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    $\begingroup$ where have you looked so far? textbooks? primary literature? can you give some specifics? $\endgroup$
    – Vance L Albaugh
    Oct 11, 2016 at 16:04
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    $\begingroup$ This should be covered to some extent in almost any textbook on molecular biology. One excellent book is Mark Ptashne's "A Genetic Switch". It's about regulation in lambda phage, a virus, but many of the principles cary over to prokaryotes as well. It has a full chapter devoted to a detailed analysis of the experiments used to identify the transcription factors and promoters. $\endgroup$
    – Charles E. Grant
    Oct 11, 2016 at 18:23
  • $\begingroup$ This is one of the things I looked at: ibiology.org/ibioeducation/exploring-biology/molecular-biology/… But a lot of things I read was about the methods and discoveries, without much detail really on what people were thinking when they tried these things out. $\endgroup$
    – Cedar
    Oct 11, 2016 at 18:35
  • $\begingroup$ @CharlesE.Grant Got it. I will check it out. $\endgroup$
    – Cedar
    Oct 11, 2016 at 18:38
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    $\begingroup$ If your final goal is to understand how to carry out your project then you can focus on how such studies are carried out in current times. Scientific research in earlier times were limited by the technology available at that time. $\endgroup$
    – WYSIWYG
    Oct 12, 2016 at 6:06

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As it can be seen from (more or less recent) discovery, most of the regulators were discovered through specifically designed experiment to exhibit one particular factor. Several examples include:

  • The discovery of Sp1, the first eukaryote transcription factor to be discovered (as described in the video linked in the comments)
  • The discovery of the Lac operon in E. coli.

None of these were intended to be screens for regulatory sequences in general. If you are looking for regulatory sequences of a specific gene, the technique of reporter gene, combined for instance with a random mutagenesis screening can provide you with a mapping of regulatory elements.

The following article might be of interest to perform a screen based on UV-mutagenesis: UV mutagenesis in Escherichia coli K-12: Cell survival and mutation frequency of the chromosomal genes lacZ, rpoB, ompF, and ampA.

If your question is more general: "all the regulatory sequences associated with one gene", then this question is generally unanswered, and can probably be better tackled first using bioinformatics analysis (such as promoter prediction, etc).

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