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, 21 (4), 359-368

Genetic and Epigenetic Editing in Nervous System

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Genetic and Epigenetic Editing in Nervous System

Jeremy J Day. Dialogues Clin Neurosci.

Abstract

Numerous neuronal functions depend on the precise spatiotemporal regulation of gene expression, and the cellular machinery that contributes to this regulation is frequently disrupted in neurodevelopmental, neuropsychiatric, and neurological disease states. Recent advances in gene editing technology have enabled increasingly rapid understanding of gene sequence variation and gene regulatory function in the central nervous system. Moreover, these tools have provided new insights into the locus-specific functions of epigenetic modifications and enabled epigenetic editing at specific gene loci in disease contexts. Continued development of clustered regularly interspaced short palindromic repeats (CRISPR)-based tools has provided not only cell-specific modulation, but also rapid induction profiles that permit sophisticated interrogation of the temporal dynamics that contribute to brain health and disease. This review summarizes recent advances in genetic editing, transcriptional modulation, and epigenetic reorganization, with a focus on applications to neuronal systems and potential uses in brain disorders characterized by genetic sequence variation or transcriptional dysregulation. .

Keywords: CRISPR/Cas9; epigenetic editing; gene regulation; neuroepigenetics; transcription.

Figures

Figure 1.
Figure 1.. Relationship between temporal precision and genetic precision of available technologies for chromatin and transcriptional regulation. CRISPR-dCas9 tools offer unprecedented genomic precision, and recent adaptations in this technology have also enabled improved temporal control of gene expression and epigenetic editing.
Figure 2.
Figure 2.. Emerging toolbox for genetic and temporal precision of CRISPR-Cas9 based approaches for studying gene 
regulation. a, Top, use of CRISPR-Cas9 protein to induce double-strand breaks (DSB) at specific sites based on complementarity of the sgRNA target and location of a protospacer-adjacent motif (PAM). Bottom, catalytically inactive dCas9 protein creates a modular genomic anchor for fused effector proteins. b, dCas9-effector toolbox enables robust bidirectional transcriptional regulation, epigenetic editing of chromatin or DNA, fusion of modular scaffolds or fluorescent proteins, and recruitment of long non-coding RNAs. c, Strategies for genetic, chemical, and light-activated control of dCas9-effector expression and/or localization. See text for details and abbreviations.

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