The Regulatory Genome

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1. 100ideasApr 2016
   Eukaryotic cells solve the "crosstalk problem" by building the control regions that regulate gene expression out of modular, hierarchically-organized binding sites for multiple transcription factors (TFs).

   In prokaryotic systems there is (in a very approximate, generic sense) a one-to-one correspondence between the concentration of a particular transcription factor and the expression (or repression) of the genes downstream of the binding site for that transcription factor.

   The control regions in eukaryotic genomes have binding sites for multiple transcription factors, combinations of which may become binding sites for other transcription factors (larger TFs which bind to certain combinations of smaller TFs), etc.

   In this way, the specific sequence of TF binding domains in the regulatory region of a eukaryotic gene provides a particular and potentially unique "address" in "Transcription Factor State Space" by which the gene can be controlled.

   For more information on this amazing topic, check out "The Regulatory Genome" by Eric H. Davidson. Here is an excerpt from the first page of chapter 4:

   "Whatever their extent, however, development gene regulatory networks have an internal structure, in that they are composed of diverse kinds of modular parts and connections among these parts. Here 'modular' takes on a simple functional meaning: it is used to denote small subsets of genes within the overall network that together execute given 'jobs,' e.g., to operate a certain differentiation gene battery, or to transduce an extracellular signal into a certain regulatory state.

   In what follows, sets of regulatory genes that execute modular functions are usually referred to as constituting 'subcircuits' of the network, because as we shall shortly see they are 'wired together' within the subcircuit by their gene regulatory interactions. Just as the target site inputs of an individual cis-regulatory [note: cis- prefix in this context indicates gene regulation via non-expressed sequences of DNA proximal to a gene in the genome] module are integrated to generate novel outputs according to its genomic design, so the outputs of these subcircuits are integrated to generate logic outputs which depend on their organization, that is, their wiring architecture."

   - https://books.google.com/books?id=F2ibJj1LHGEC&pg=PA126

   [edit 1: added link to google books & excerpt]

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2. bra-ketJul 2014
   The Regulatory Genome: Gene Regulatory Networks In Development And Evolution, by Eric Davidson

   awesome read.

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3. 100ideasNov 2017
   Also:

   Istrail S, De-Leon SB, Davidson EH. The regulatory genome and the computer. Dev Biol. 2007 Oct 15;310(2):187-95. Epub 2007 Aug 10. Review. PubMed PMID: 17822690. Full-text: http://www.sciencedirect.com/science/article/pii/S0012160607...

   Abstract:

   > "The definitive feature of the many thousand cis-regulatory control modules in an animal genome is their information processing capability. These modules are “wired” together in large networks that control major processes such as development; they constitute “genomic computers.” Each control module receives multiple inputs in the form of the incident transcription factors which bind to them. The functions they execute upon these inputs can be reduced to basic AND, OR and NOT logic functions, which are also the unit logic functions of electronic computers. Here we consider the operating principles of the genomic computer, the product of evolution, in comparison to those of electronic computers. For example, in the genomic computer intra-machine communication occurs by means of diffusion (of transcription factors), while in electronic computers it occurs by electron transit along pre-organized wires. There follow fundamental differences in design principle in respect to the meaning of time, speed, multiplicity of processors, memory, robustness of computation and hardware and software. The genomic computer controls spatial gene expression in the development of the body plan, and its appearance in remote evolutionary time must be considered to have been a founding requirement for animal grade life."

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