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Design principles of biological circuits
Cells are constantly "making decisions" - monitoring their environment, modulating their metabolism and 'deciding' whether to divide, differentiate or die. For this, they use biochemical circuits composed of interacting genes and proteins. Advances over the past decades have mapped many of these circuits. Still, can we infer the underlying logic from the detailed circuit structure? Can we deduce the selection forces that shaped these circuits during evolution? What are the principles that govern the design and function of these circuits and how similar or different are they from principles that guide the design of man-made machines? The interplay between variability and robustness is a hallmark of biological computation: Biological systems are inherently noisy, yet control their behavior precisely. Research projects in our lab quantify biological variability and identify its genetic origins, examine how variability is buffered by molecular circuits and investigate whether variability can in fact be employed to improve cellular computation. We encourage a multi-disciplinary approach, combining wet-lab experiments, dynamic-system theory and computational data analysis. This is achieved through fruitful interactions between students with backgrounds in physics, biology, computer science, mathematics and chemistry.



Meyer bulding 404
Weizmann Institute of Science
Rehovot 76100

Epigenetic Control of Expression Homeostasis during Replication Is Stabilized by the Replication Checkpoint
Yoav Voichek*, Karin Mittelman*, Yulia Gordon, Raz Bar-Ziv, David Lifshitz Smit, Rom Shenhav, Naama Barkai
Molecular Cell (2018)

DNA replication introduces a dosage imbalance between early and late replicating genes. In budding yeast, buffering gene expression against this imbalance depends on marking replicated DNA by H3K56 acetylation (H3K56ac). Whether additional processes are required for suppressing transcription from H3K56ac-labeled DNA remains unknown. Here, using a database-guided candidate screen, we find that COMPASS, the H3K4 methyltransferase, and its upstream effector, PAF1C, act downstream of H3K56ac to buffer expression. Replicated genes show reduced abundance of the transcription activating mark H3K4me3 and accumulate the transcription inhibitory mark H3K4me2 near transcription start sites. Notably, in hydroxyurea-exposed cells, the S phase checkpoint stabilizes H3K56ac and becomes essential for buffering. We suggest that H3K56ac suppresses transcription of replicated genes by interfering with post-replication recovery of epigenetic marks and assign a new function for the S phase checkpoint in stabilizing this mechanism during persistent dosage imbalance.Read more...

Departments of Molecular Genetics and Physics of Complex Systems