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Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
Published on: September 20, 2018
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Rapid and reversible epigenome editing by endogenous chromatin regulators
Simon M G Braun1, Jacob G Kirkland1, Emma J Chory1,2
1Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Nature Communications
|September 17, 2017
Summary
Scientists created FIRE-Cas9, a tool for rapid, reversible epigenetic editing. This system precisely recruits chromatin regulators to control gene transcription and study epigenetic memory in mammalian cells.
Area of Science:
- Chromatin biology
- Epigenetics
- Gene regulation
Background:
- Understanding the causal link between epigenetic marks and gene regulation is crucial in chromatin biology.
- Developing tools for direct chromatin manipulation is essential for studying epigenetic mechanisms.
Purpose of the Study:
- To develop a system for rapid and reversible recruitment of endogenous chromatin regulators to specific genomic loci.
- To investigate the effects of targeted chromatin regulator recruitment on gene transcription and epigenetic states.
Main Methods:
- Developed the FIRE-Cas9 system, enhancing dCas9-MS2 with FKBP/FRP dimerizing fusion proteins for chemical-induced proximity.
- Recruited mSWI/SNF (BAF) complex and Hp1/Suv39h1 heterochromatin complex to specific genomic loci in mouse embryonic stem cells.
Main Results:
- Recruitment of mSWI/SNF (BAF) complex rapidly opposed Polycomb, activating bivalent gene transcription.
- Recruitment of Hp1/Suv39h1 complex deposited H3K9me3, causing gene silencing reversible upon chemical dimerizer washout.
- Demonstrated precise kinetic information for modeling epigenetic memory and plasticity.
Conclusions:
- The FIRE-Cas9 system enables rapid, reversible manipulation of epigenetic states.
- This inducible recruitment strategy is broadly applicable for mechanistic studies of chromatin regulators in mammalian cells.
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