Application of CRISPR/Cas9 to the study of brain development and neuropsychiatric disease

doi:10.1016/j.mcn.2017.05.007

Molecular and Cellular Neuroscience

Volume 82, July 2017, Pages 157-166

https://doi.org/10.1016/j.mcn.2017.05.007 Get rights and content

Highlights

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CRISPR/Cas9 techniques to study neurodevelopment.
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CRISPR/Cas9 applications to hiPSC-based models of neuropsychiatric disease.
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The potential for CRISPR/Cas9 approaches to advance our understanding of psychiatric illnesses.

Abstract

CRISPR/Cas9 technology has transformed our ability to manipulate the genome and epigenome, from efficient genomic editing to targeted localization of effectors to specific loci. Through the manipulation of DNA- and histone-modifying enzyme activities, activation or repression of gene expression, and targeting of transcriptional regulators, the role of gene-regulatory and epigenetic pathways in basic biology and disease processes can be directly queried. Here, we discuss emerging CRISPR-based methodologies, with specific consideration of neurobiological applications of human induced pluripotent stem cell (hiPSC)-based models.

Section snippets

Epigenetics in neuropsychiatric disease

Increasing evidence supports a strong role for transcriptional and epigenetic abnormalities in the development of neurological (Jakovcevski and Akbarian, 2012) and psychiatric (Peña et al., 2014) diseases. Epigenetic mechanisms, such as DNA and histone post-translational modifications, non-coding RNA-mediated processes, and higher order chromatin structure dynamics regulate a wide variety of neuronal processes and modulate susceptibility to neuropsychiatric illnesses (McGill and Zoghbi, 2014,

Introduction to CRISPR/Cas9

The clustered, regularly interspaced short palindromic repeats (CRISPR)/Cas (CRISPR-associated protein) system allows targeted and specific genetic manipulation. It was initially discovered as a key defense mechanism against invading viruses and plasmids in several bacterial species and Archaea (well reviewed in Wang et al., 2016). When microorganisms incorporate invading DNA sequences into their genomes, these sequences are transcribed into CRISPR RNAs (crRNAs) (Ishino et al., 1987) that, when

Applications of CRISPR/Cas9 to study transcriptional and epigenetic mechanisms underlying disease processes

CRISPR/Cas9 can be used to modulate expression of histone- and DNA-modifying enzymes, alter DNA-binding sites of factors that regulate transcription, perturb non-coding RNA expression, modify non-coding gene-regulatory regions, and manipulate higher-order chromatin structure. In this section, we focus on the application of CRISPR/Cas9 to study gene regulatory and epigenetic pathways in neurobiology contexts.

Applications of CRISPR/Cas9 techniques to human induced pluripotent stem cell models

In this section, we provide a brief overview of human induced pluripotent stem cell (hiPSC)-based models and highlight recent advances in the field that have used CRISPR/Cas9 strategies to study gene-regulatory processes in neuropsychiatric disease.

Future directions

In the next section, we discuss ways in which advances in CRISPR/Cas9 technology may further expand our understanding of neuropsychiatric disease. See Fig. 2 for an illustration of these processes.

Summary

Neurological and psychiatric diseases frequently involve pathogenic alterations in gene-regulatory and epigenetic processes. With the advent of CRISPR/Cas9, targeted manipulation of a variety of regulatory factors, non-protein-coding sequences, and non-coding RNAs can now explore the role of these pathways in neuropsychiatric conditions. Future approaches will expand the ability of CRISPR/Cas9 to effect specific perturbations in epigenetic pathways. By applying these new tools to a variety of

Acknowledgments

Kristen Brennand is a New York Stem Cell Foundation - Robertson Investigator. This work was partially supported by National Institutes of Health (NIH) grants R01 MH101454 (KJB) and R01 MH106056 (SA) and P50 MH096890 (SA), as well as the New York Stem Cell Foundation and the Brain & Behavior Research Foundation.

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The neuroscience and neurobiology of gene editing to enhance learning and memory is of paramount interest to the scientific community. The advancements of CRISPR system have created avenues to treat neurological disorders by means of versatile modalities varying from expression to suppression of genes and proteins. Neurodegenerative disorders have also been attributed to non-canonical DNA secondary structures by affecting neuron activity through controlling gene expression, nucleosome shape, transcription, translation, replication, and recombination. Changing DNA regulatory elements which could contribute to the fate and function of neurons are thoroughly discussed in this review. This study presents the ability of CRISPR system to boost learning power and memory, treat or cure genetically-based neurological disorders, and alleviate psychiatric diseases by altering the activity and the irritability of the neurons at the synaptic cleft through DNA manipulation, and also, epigenetic modifications using Cas9. We explore and examine how each different OMIC techniques can come useful when altering DNA sequences. Such insight into the underlying relationship between OMICs and cellular behaviors leads us to better neurological and psychiatric therapeutics by intelligently designing and utilizing the CRISPR/Cas9 technology.
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Application of CRISPR/Cas9 to the study of brain development and neuropsychiatric disease

Highlights

Abstract

Section snippets

Epigenetics in neuropsychiatric disease

Introduction to CRISPR/Cas9

Applications of CRISPR/Cas9 to study transcriptional and epigenetic mechanisms underlying disease processes

Applications of CRISPR/Cas9 techniques to human induced pluripotent stem cell models

Future directions

Summary

Acknowledgments

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A review of Rett syndrome (RTT) with induced pluripotent stem cells

Stem Cell Investig.

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PLoS One

Histone chaperone CHAF1A inhibits differentiation and promotes aggressive neuroblastoma

Cancer Res.

Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology

Mol. Psychiatry

Clustered regularly interspaced short palindrome repeats (CRISPRs) have spacers of extrachromosomal origin

Microbiology

Modelling schizophrenia using human induced pluripotent stem cells

Nature

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Nature

The DISC locus in psychiatric illness

Mol. Psychiatry

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Nucleic Acids Res.

Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells

Nat. Genet.

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Nature

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Nature

Genome editing. The new frontier of genome engineering with CRISPR-Cas9

Science

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Nat. Neurosci.

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Curr. Protoc. Stem Cell Biol.

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Nat. Med.

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Nature

Etiology of autism: genetic influences

Pediatrics

Regulation of chromatin accessibility and Zic binding at enhancers in the developing cerebellum

Nat. Neurosci.

Gene expression elucidates functional impact of polygenic risk for schizophrenia

Nat. Neurosci.