Team:UCSF/Project

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Overall project

The goals of synthetic biology are to gain a deeper understanding of native biological systems, as well as to develop new ones. In doing so, most devices and systems have been constructed by co-opting 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 may 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 around nucleosomes, "spools" that consist of an octamer of histone proteins. The DNA and protein together, termed chromatin, can be tightly packgaged (heterochromatin) or more loosely arranged (eucharomatin). The density of nucleosomal packaging is indicated by a host of histone modifying enzymes, and enforced by chromatin remodeling complexes. Euchromatin is accessible by the transcriptional machinery and thus can be transcribed (active), while heterochromatin is inaccessible, and refractory to transcription (silenced).

In nature, the modulation of gene expression via the alteration of the physical structure of DNA is an incredibly powerful form of cellular memory. Indeed, epigenetic changes regulating genome-wide expression patterns can persist through multiple rounds of cell division and remain for the lifetime of the cell. This mechanism allows embryonic stem cells to differentiate into myriad cell types in higher eukaryotes.

For our project, we are establishing, characterizing and standardizing methods to engineer epigenetic control 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 devising 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 memory (i.e. persistence past a transient stimulus)
control and measure the regional spread of heterochromatin
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

Home	The Team	The Project	Parts Submitted to the Registry	Modeling	Notebook

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 == '''Overall project''' ==
-The goals of synthetic biology have been framed to both gain a deeper understanding of the native biological systems, as well as to develop 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.
+The goals of synthetic biology are to gain a deeper understanding of native biological systems, as well as to develop new ones.  In doing so, most devices and systems have been constructed by co-opting 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 may 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).
+'''This year, our team is attempting to engineer the epigenetic control of gene expression.'''  In eukaryotic cells, DNA is wound around nucleosomes, "spools" that consist of an octamer of histone proteins. The DNA and protein together, termed chromatin, can be tightly packgaged (heterochromatin) or more loosely arranged (eucharomatin). The density of nucleosomal packaging is indicated by a host of histone modifying enzymes, and enforced by chromatin remodeling complexes.  Euchromatin is accessible by the transcriptional machinery and thus can be transcribed (active), while heterochromatin is inaccessible, and refractory to 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.
+In nature, the modulation of gene expression via the alteration of the physical structure of DNA is an incredibly powerful form of cellular memory. Indeed, epigenetic changes regulating genome-wide expression patterns can persist through multiple rounds of cell division and remain for the lifetime of the cell.  This mechanism allows embryonic stem cells 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:
+For our project, we are establishing, characterizing and standardizing methods to engineer epigenetic control 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 devising 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
+*create silencing/activation with memory (i.e. persistence past a transient stimulus)
-*control and measure the regional space of synthetic remodeling
+*control and measure the regional spread of heterochromatin
 *initiate silencing or activation through various extracellular cues
 *link this to distinct biological outputs