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REVIEW
Editing the epigenome: technologies for programmable transcription and epigenetic modulation
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Virtually any DNA sequence can be targeted with new customizable epigenome-engineering tools that regulate gene expression by modifying transcription and/or epigenetic state. Making site-specific alterations to the epigenomic landscape in eukaryotic cells is a powerful strategy for interrogating the mechanistic relationships among chromatin state, gene regulation, and cell phenotype. Furthermore, control over gene regulation is a valuable tool for applications such as gene therapy and reprogramming cell fate (Fig. 1).
Principles of transcriptional and epigenetic regulation in mammalian cellsEukaryotic mRNA transcription is guided by interactions among the RNA polymerase II holoenzyme (Pol II), associated transcription factors, and genomic regulatory elements1. Transcriptionally active promoters are generally characterized by an accessible chromatin state that is amenable to binding by activating
Pratiksha I Thakore1,2, Joshua B Black1,2, Isaac B Hilton1,2 & Charles A Gersbach13
Gene regulation is a complex and tightly controlled process that denes cell identity, health and disease, and response to pharmacologic and environmental signals. Recently developed DNA-targeting platforms, including zinc nger proteins, transcription activator-like effectors (TALEs) and the clustered, regularly interspaced, short palindromic repeats (CRISPR)-Cas9 system, have enabled the recruitment of transcriptional modulators and epigenome-modifying factors to any genomic site, leading to new insights into the function of epigenetic marks in gene expression. Additionally, custom transcriptional and epigenetic regulation is facilitating rened control over cell function and decision making. The unique properties of the CRISPR-Cas9 system have created new opportunities for high-throughput genetic screens and multiplexing targets to manipulate complex gene expression patterns. This Review summarizes recent technological developments in this area and their application to biomedical challenges. We also discuss remaining limitations and necessary future directions for this eld.
transcription factors2. Promoter activity also can be affected by local and distal regulatory elements1,3,4.
Chemical modifications to DNA and associated his-tone proteins govern chromatin accessibility, and regulatory elements demonstrate dynamic signatures of these modifications that correlate with their activity in different cell states and types49 (Table 1). The causal relationships between histone and DNA modifications and transcription are complex and incompletely understood, and exhaustive mapping of the eukaryotic histone code has only just begun4,10,11.
Coordinated efforts to annotate eukaryotic epigenomes have revealed the complex layer...