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Sci Rep. 2016 Jun 24;6:28420. doi: 10.1038/srep28420.

Precision Modulation of Neurodegenerative Disease-Related Gene Expression in Human iPSC-Derived Neurons.

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Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3QX, UK.
NIH Oxford-Cambridge Scholars Program, National Institutes of Health, Bethesda, MD, 20892, US.
UNC MD-PhD Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, US.
Genome Engineering Oxford, Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK.


The ability to reprogram adult somatic cells into induced pluripotent stem cells (iPSCs) and the subsequent development of protocols for their differentiation into disease-relevant cell types have enabled in-depth molecular analyses of multiple disease states as hitherto impossible. Neurons differentiated from patient-specific iPSCs provide a means to recapitulate molecular phenotypes of neurodegenerative diseases in vitro. However, it remains challenging to conduct precise manipulations of gene expression in iPSC-derived neurons towards modeling complex human neurological diseases. The application of CRISPR/Cas9 to mammalian systems is revolutionizing the utilization of genome editing technologies in the study of molecular contributors to the pathogenesis of numerous diseases. Here, we demonstrate that CRISPRa and CRISPRi can be used to exert precise modulations of endogenous gene expression in fate-committed iPSC-derived neurons. This highlights CRISPRa/i as a major technical advancement in accessible tools for evaluating the specific contributions of critical neurodegenerative disease-related genes to neuropathogenesis.

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