Holistic approach to the bacterial genetic regulation system

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Exploration of the bacterial genetic regulation system is central for the advancement of both systems and synthetic biology and for establishing efficient knowledge-based approaches in biotechnology and biomedicine. Vigorous international research employing high-throughput technologies revealed the true complexity of the problem and a critical need for an appropriate methodological approach integrating different structural and organisational features of the genetic regulation system. At the bottom line, the major requirement is to understand the control of information flow in the genetic system. We have developed a new holistic methodology integrating the DNA sequence organization, DNA topology, gene order, gene function and the dynamics of interactions between the regulators and their targets in chromosomal macrodomains. Using this methodology we recently provided a first mechanistic insight into how the organization of a complete bacterial chromosome encodes a spatiotemporal program integrating DNA replication and global gene expression. Our work illuminated why the timing of the expression of a gene is linked to its position on the bacterial chromosome and provided a view of the nucleoid as a highly organized dynamic entity optimized for coordinating oxygen and nutrient availability with spatiotemporal gene expression during rapid growth and its cessation. The prediction is that during the bacterial growth cycle reorganization of transcription is driven by a spatiotemporal gradient of DNA superhelical density from the origin to terminus of chromosomal replication. This gradient is modulated by compositional changes of the abundant nucleoid-associated proteins (NAPs), which constrain DNA supercoils in variable chromosomal regions thus coordinately reorganizing the chromosomal shape and transcription. The observed regional effects on transcription in the bacterial chromosome suggest that strategic positioning of regulatory genes may provide new powerful means for controlling bacterial gene expression and adaptation. The work intended in this project aims to provide such novel tools crucial for implementing knowledge-based approaches in a range of related fields concerned with both fundamental and applied aspects of the bacterial gene regulation.