Genetic Networks

Abstract

Genetic networks control the execution of the genetic program stored in an organism's deoxyribonucleic acid (DNA) by orchestrating gene expression. Any biological function, in physiology or development, is dependent on the combined action of many genes, requiring their precise control. Expression of individual genes is determined by associated regions of regulatory DNA. These are bound by sequence‐specific regulatory proteins, called transcription factors, leading to activation or repression of transcription. The interactions among regulatory genes display the features of a network where the linkages are determined by the binding sites in the regulatory region of downstream genes. The architecture of genetic networks is intrinsically hierarchical, and discrete subcircuits that accomplish particular tasks can be identified. Certain linkage patterns are recurrent in subcircuits with similar biological function, although the regulatory genes involved differ. This suggests that the topology of the network, and not the identity of its constituents, determines the function.

Key Concepts

  • Genomic sequence determines the phenotype by specifying the amino acid sequence of proteins and their timing of expression.
  • Regulation of gene expression occurs primarily at the level of transcription.
  • Regulatory genes are sequence‐specific transcription factors that activate or repress transcription and signalling molecules that affect transcriptional activity in receiving cells.
  • Modular arrays of transcription factor target sites within the cis‐regulatory domains of genes determine the transcription of individual genes.
  • A genetic network is a set of regulatory genes that are functionally linked through sequence‐specific interactions.
  • Each regulatory interaction is contingent on the state of other interactions in the network.
  • Recurrent linkage patterns indicate that the network topology and not identity of individual regulators determines the biological function.
  • In development, the regulatory processes at each stage determine what will happen next, leading to progressive partitioning of the embryo, and ensuring that development is unidirectional.
  • Changes in network architecture are the underlying cause of phenotypic changes in evolution.

Keywords: transcription; gene regulation; network topology; DNA binding; information processing; intercellular signalling; development; patterning; logic function; gene regulatory network

Figure 1. Gene regulatory domains are modular. (a) In a hypothetical example, the gene is represented by a horizontal line and the transcription start site by the bent red arrow. Coloured shapes represent the proteins bound to the DNA at their specific binding sites. The activity of the basal transcription apparatus (BTA) is positively affected by the proteins bound at sites TGTGT and CCAAT and negatively by the protein bound at site TACGG (orange lines). The proteins bound at sites GGGG interact with each other, causing the DNA to loop and thereby facilitating the interactions between the other regulatory proteins and the BTA (blue lines). (b) Modular gene regulation in neural crest cells. The transcription of the foxD3 gene in the neural crest of chickens (shaded blue area of schematised chick embryo, anterior to the right) is controlled by two regulatory modules, NC1 and NC2. Both receive the transcription factors Msx and Pax7, which are expressed throughout the entire neural crest (red bar below), as activating inputs. NC1 also requires binding of Ets1, but its expression is restricted to the head region (blue bar), thus restricting activity of this module to the cranial neural crest. NC2 is bound by the Zic1 protein that is present in the trunk neural crest (green bar), driving FoxD3 expression there.
Figure 2. Organisational level of genetic networks. Regulatory modules are short stretches of sequence that contain binding sites for transcription factors that determine whether transcription of the gene they control is initiated. Several regulatory modules (white boxes), each controlling a discrete feature of the overall expression pattern, may be associated with a gene. Genes with more complex expression patterns usually contain more regulatory modules. Genes A and B are connected in a positive feedback loop, and both are direct activating inputs into the regulatory module of gene A, as confirmed by the presence of their binding sites. Simple network motifs as feedback loops are the building blocks of genetic networks and are used in combination to implement particular functions. In this simple example, their mutual activation ensures that the input from gene C is required only transiently. A unique combination of genes is connected in a network subcircuit to achieve a particular biological function. The subcircuit depicted here locks down the regulatory state and leads to expression of genes D and E. Expression of gene E prevents activation of gene F, excluding alternative fates.
Figure 3. Examples of genetic network subcircuits that pattern embryonic tissues. (a) In the ectoderm of sea urchin embryos, the SoxB1 transcription factor is an activating input into the nodal and emx genes. Initially, both genes are expressed in overlapping patterns (cross‐hatched area in 12 h postfertilisation embryo (hpf)). Nodal is a signalling ligand that activates the lefty and not1 genes. Lefty antagonises Nodal signalling and limits nodal and not1 expression to the central domain (C) of the ventral ectoderm, where later the mouth will form. Not1 represses transcription of the emx gene, thus excluding its expression from the central domain. In consequence, emx expression is relegated to the lateral domain (L) by 24 hpf and two distinct domains have been established. (b) In the neural tube of vertebrates, the signalling ligand Sonic Hedgehog (Shh) is expressed in the most ventral compartment. It diffuses dorsally into the neural tube (indicated by double arrows) that initially uniformly expresses Pax6. Shh activates expression of several transcription factors that regulate each other as summarised in the wiring diagram on the right. These interactions determine the progression of regulatory states (top to bottom) depicted here as observed in the compartment directly adjacent to the floor plate (black arrow in top panel), where nkx2.2 expression comes to dominate.
Figure 4. Genetic network control of morphogenetic events. (a) Subcircuit controlling migration of heart progenitors in the sea squirt Ciona intestinalis. The mesodermal progenitor cells (purple patches) are located in two lateral patches of four cells at the anterior end of the trunk. They express Mesp, which controls transcription of Ets.b. FGF signalling in the trunk is received in the two anterior progenitor cells where it activates Ets.b through phosphorylation, leading in turn to initiation of FoxF transcription. In consequence, the Rho GTPase RhoDF is activated in the two anterior cells, which affects actin cytoskeleton dynamics and thus promotes migration of trunk ventral cells (TVC, red patch). The cells left behind differentiate into anterior tail muscles (ATM). (b) Process diagram for neural crest development in vertebrates. Neural crest specification is set in motion by first demarcating the neural plate border region downstream of various signalling inputs. As the neural tube forms, neural crest‐specific genes are activated along the ectodermal ridges (green, top panel) that in turn lock down the neural crest‐specific regulatory state. The neural crest specification genes cause cells to become migratory and undergo epithelial‐to‐mesenchyme transition. Migrating neural crest cells express a new set of regulatory genes that determine their behaviour according to their position along the body axis and presage what they will eventually differentiate into.
Figure 5. Recurring subcircuit architectures in developmental genetic networks. (a) Positive feedback loops stabilise regulatory states by transforming transient inputs into stable outcomes. (b) Coherent feed forward subcircuits integrate inputs. Activation of C is contingent on A and B but may be delayed. (c) Incoherent feed forward subcircuits are used for spatial subdivision as in the examples in Figure. This circuitry can also be used to cause a burst of expression of gene C, which is quickly shut off. (d) Reciprocal repression circuits prevent establishment of alternative regulatory states. These are often employed in cells descendent from a common progenitor to extinguish alternative regulatory states. (e) Toggle switch wiring ensures binary outcomes of signalling events. The immediate effectors of many signalling systems, for example Notch or Hedgehog (Figure), function as repressors in the absence of signal leading to a switch‐like behaviour. (f) Double negative gate architecture is a device ensuring that genes are activated in only a particular domain but off elsewhere.
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References

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Further Reading

Alon U (2007) Network motifs: theory and experimental approaches. Nature Reviews Genetics 8: 450–461. DOI: 10.1038/nrg2102.

Peter I and Davidson EH (2015) Genomic Control Process. Oxford: Academic Press.

Ptashne M (2004) A Genetic Switch. New York: CSHL Press.

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Materna, Stefan C, and Woo, Stephanie(Jun 2018) Genetic Networks. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001170.pub3]