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Team:UCSF/Project
From 2008.igem.org
Overall project
The goals of synthetic biology have been framed to both gain a deeper understanding of the endogenous biological systems, as well as to construct new ones. In doing so, most exogenous devices and systems have been constructed using traditional genetic elements, where transcriptional activators and/or repressors modulate the transcription of protein encoding regions. While this has proved useful and reliable for synthetic systems, other biological mechanisms provide additionally robust behaviors that synthetic biologists have yet to explore and take advantage of.
This year, our team is attempting to engineer the epigenetic control of gene expression. In eukaryotic cells, DNA is wound and organized with histone proteins into chromatin units called nucleosomes. The density of nucleosomal packaging is regulated by a host of histone modifying enzymes, chromatin remodeling complexes, and, frequently, DNA methylation. DNA located in loosely packed chromatin, or euchromatin, is generally more easily accessed by transcriptional machinery and thus more easily transcribed (active), while in tightly packed and highly ordered heterochromatin, it is inaccessible for transcription (silenced).
Endogenously, the modulation of gene expression via the alteration of the physical structure of DNA creates an incredibly powerful form of cellular memory—these changes may last through multiple rounds of cell division and remain for the lifetime of the cell. This mechanism is what allows a single totipotent zygote to differentiate into myriad cell types in higher eukaryotes.
For our project, we are establishing, characterizing and standardizing methods to engineer cellular memory in the eukaryotic yeast Saccharomyces cerevisiae. To do so, we are taking endogenous proteins known to modify chromatin structure, such as Sir2, an NAD+ dependent histone deacetylase, and engineering methods to control and direct their activity. We are concentrating on generating a chromatin toolkit that can:
- silence (or “close”) euchromatin
- activate (or “open”) heterochromatin
- create silencing/activation with complete permanence
- control and measure the regional space of synthetic remodeling
- initiate silencing or activation through various extracellular cues
- link this to distinct biological outputs
We believe that the ability to control the structure of chromatin will allow synthetic biologists to engineer robust systems with novel and predictable behaviors. We look forward to introducing and discussing these ideas in November!
Project Details
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