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Cracking the regulatory code: predicting expression patterns from DNA sequence

Segal, E (Weizmann Institute)
Thursday 03 April 2008, 09:00-10:00

Seminar Room 1, Newton Institute


Precise control of gene expression lies at the heart of nearly all biological processes. However, despite enormous advances in understanding this process from both experimental and theoretical perspectives, we are still missing a quantitative description of the underlying transcriptional control mechanisms, and the remaining questions, such as how regulatory sequence elements ‘compute’ expression from the inputs they receive, are still very basic.

In this talk, I will present our progress towards the ultimate goal of developing integrated quantitative models for transcription regulation, spanning all aspects of the process, including the DNA sequence, regulators, and expression patterns. I will first describe a novel thermodynamic model that computes expression patterns as a function of cis-regulatory sequence and the binding site preferences and expression of participating transcription factors. I will show that when applied to the segmentation gene network of Drosophila, the model accurately predicts the expression of many known cis-regulatory modules, even across species, and reveals important organizing principles of transcriptional regulation in the network: that both strong and large numbers of weaker binding sites contribute, leading to high occupancy of the module DNA, and conferring robustness against mutation; and that clustering of weaker sites permits cooperative binding, which is necessary to sharpen the patterns.

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