Toward Systems Biology

May 30 - 31, June 1, 2011

Grenoble

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From the Operon Theory to Epigenetics: a trip of 50 years into gene regulation

The Operon model proposed by Fran├žois Jacob and Jacques Monod in their May 1961 publication in the Journal of Molecular Biology (3, 318-356) laid the grounds for the concept that the expression of genes in bacteria is regulated. It postulated for the first time the existence of two classes of genes: structural genes that encode for metabolic enzymes and the building blocks of the cell and regulatory genes that encode for RNA or proteins with regulatory functions. The initial model postulated negative regulation by repression of transcription. Genes are shut off by a repressor RNA or protein, when their product is not essential and induced by their substrate as for the classical beta galactosidase.

Slightly later it became apparent that in several systems that regulation is not negative but rather positive. Genes are induced when the regulator protein is bound by the substrate for an enzyme, e.g. arabinose or maltose. Even for the beta galactosidase gene, in addition to repression, it requires a positive regulator, the CAP or cAMP binding protein, which confers the sensitivity to excess glucose. The repressor blocks the progression of the RNA polymerase while camp bound CAP helps recruitment and progression of the polymerase. The juxtaposition of negative and positive regulators increases the sensitivity and graduation of the response. Another way to render transcription control more complex is to require that multiple protein cooperate in recruitment/initiation by the polymerase and to use proteins that will specifically bend DNA to facilitate protein-protein contacts. Another way to control the activity of transcription regulators is their covalent modification, e.g. phosphorylation.

Moving from bacteria to unicellular or multi-cellular eukaryotes the system becomes more complex. Eukaryotes pack their DNA in chromatin, consisting of a repeat structure of 146 base pairs of DNA and 8 molecules of histones. This structure constitutes a barrier for protein DNA recognition and for polymerase progression.

Transcription initiation frequently requires many more gene specific and general transcription factors. Frequently transcription factors act as positive regulators and their activity depends on covalent modifications, mostly phosphorylation. This increases the sensitivity of transcription to signal transduction pathways that transmit signal from the outer membrane of the cell.

Both initiation and elongation require chromatin modifications that are achieved by histone covalent modifications and the recruitment of chromatin remodelling ATP dependent machines. Gene specific transcription factors have a role both in the recruitment of the basal (general) transcription factors and of chromatin modifiers and remodelers. This adds an extra layer for gene control. In certain regions of the genome the DNA is packed in inactive chromatin and is refractory to transcription. Finally, recent years revealed additional steps for the control of protein synthesis. Proteins and microRNA regulate mRNA turnover and accessibility of the mRNA to the translational machinery.

These many layers of control introduce an immense variability in gene expression among different cell types and during development. It also creates a formidable task to explain or predict gene expression patterns by system biology approaches or to explain how the introduction of four master transcription factors can convert a differentiated cell into a stem cell.

Moshe Yaniv, Department of Developmental Biology, Institut Pasteur