טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKatzir Yair
SubjectCell Cycle Plasticity and Adaptation to Unforeseen
Challenges
DepartmentDepartment of Medicine
Supervisor Professor Erez Braun
Full Thesis textFull thesis text - English Version


Abstract

At a given moment only part of the genes in a cell are expressed. The proper regulation of which genes are expressed and which are repressed is crucial to cellular functionality. We placed stress on the regulatory mechanism that directs the cell cycle by providing it the added task of regulating exclusively a gene essential for histidine production. The methodology we employed to do so is known as genome rewiring ? a synthetic rewiring of the regulatory system. The cell cycle must proceed despite the multitasking that is loading its native regulatory network, and histidine production must also continue normally in order for the cell to survive. We found that individual cells adapt the relevant regulatory pathways to ensure the proper functionality of both the cell cycle and the production of histidine. This adaptation involves an observed shift in the expression of a large number of the cell’s genes. Later generations faced with the same challenge recovered much faster. Our results thus indicate that individual cells can adapt by exploring a large search space to find a solution to the challenge, even when the challenge affects a system as encapsulated as the cell cycle. We further demonstrated that the results are inherited.

In order to understand better the consequences of genome rewiring on the regulatory network we constructed a model of the cell cycle allowing to incorporate the process of genome rewiring. The results of the simulation demonstrated that redistribution of the limited regulatory proteins influenced the total duration of the cell cycle, as well as the distribution of the relative durations of its component phases. This influence depended on the node in the cell-cycle regulatory network at which we rewired the essential gene from the histidine-pathway. The results of the model provide a causal explanation to the stress to which the cells are exposed during the experiments. Furthermore, the results provide insights to more general properties of the cell cycle regulation.

The results of both the experiments and the model, point to a general mechanism that enables cellular plasticity and support evolvability in genetic networks. The cell cycle is a well conserved and tightly regulated module. Adaptation to arbitrary rewiring challenges attests to its robust and dynamic reorganization capabilities.