Modelling of regulatory logic of cis- and trans- elements
The combinatorial nature of gene regulation as modeled by Boolean network has been confirmed in experiments characterizing multi-input control of gene expression in bacteria [1,2] and in a pertinent example fruit fly development [3]. Further examples of this phenomenon are now being seen in higher vertebrates, such as the multigenic control of the immediate early gene, c-fos. C-fos, itself a transcription factor connecting to a wide variety of downstream genes [17], has been mapped for some of its inputs and rules in a transgenic mose model [4]. Constructs were prepared in which four different promoter elements, SIE, SRE, FAP, CRE have been expressed individually and in combination. The results demonstrated contrary to previous assumptions that these elements do not act independently. Mutation of any single element resulted in a loss of tissue specific and stimulusevoked gene expression. SIE, SRE, FAP and CRE therefore appear to be linked by the and operator leading the authors to propose the ITC (independent transcription complex) hypotesis. Whereas the or function could be computed by elements acting in isolation, a molecular complex is required to calculate the and function. In general, ITCs could be responsible for the physical computation of rules beyond or for Boolean networks.
An example for an inhibitory gene which outputs to a group or module of genes (pleiotropoc control) is found in the regulation of neural development. The (trans) neuron- restrictive silencer factor (NRSF) suppresses transcription of neuronal genes (neuron-specific ion channels and transporters, synaptic proteins etc.) by interacting with the (cis) neuron-restrictive silencer element (NRSE). NRSF is expressed in many nonneuronal tissues, glia and neuronal progenitors. The latter lose NRSF while maturing to neurons, concomitant to the induction of neuron-specific genes. The authors have proposed the role of NRSF as a "master gene", we prefer the term focal gene, overriding stimulatory inputs to neuron-specific genes and thereby inhibiting their expression. Inhibition of such an inhibitor, constituting activation, should then facilitate neuronal differentiation. The role of such an activator has been attributed to Hel-N1, a necessary gene for the development of the nervous system. Hel-N1 protein binds to the 3' untranslated region of the ld mRNA, which encodes a transcriptional repressor that is expressed in undifferentiated neural precursors. It is interesting to note that the regulatory mechanism involved here is not based on a DNA-protein, or protein-protein, but on a protein-DNA interaction resulting in either inhibition of translation or degradation of the mRNA. From the structural network perspective, NRSF and ld provide examples of how a canalizing function "if on, then downstream element will be off, independent of other input states," radially wired, can control a larger module of genes. Furthermore, there are copious examples for canalyzing rules in addition to those discussed here, suggesting that this ordering principle is abundantly utilized in higher vertebrate gene regulatory architectures.
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