CRISPR/Cas9-mediated genome editing in nonhuman primates

Kang, Yu; Chu, Chu; Wang, Fang; Niu, Yuyu

doi:10.1242/dmm.039982

Cited by 49 publications

(38 citation statements)

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“…We used sci-ATAC-seq reads to generate a master list of 130,525 accessible sites, the median peak number was 4,973 ( Figure S1D). These accessible sites were subsequently used to identify a total 6 of 27 cell clusters and visualized them with uniform manifold approximation and projection (UMAP) (Figure 1B and Figure S1F). The identity of these cell clusters was annotated manually by promoter accessibility of brain cell marker genes ( Figure 1C).…”

Section: Single-cell Chromatin States Define Brain Cortical Cellular mentioning

confidence: 99%

“…We next assessed how the single-cell epigenetic profiles correlate with single-cell transcriptomic profiles by applying Smart-seq2 based snRNA-seq (19) to PFC, M1 and V1 of the macaque neocortex ( Figure 1A and Figure S2A). After quality filtering and cell clustering, we profiled the transcriptome from 11,477 single-nuclei (6,949 from PFC, 1,971 from M1 and 2,557 from V1) and identified 17 distinct clusters which were displayed by UMAP visualization (Figure 2A, Figure S2B and S2C, Table S1). Based on the known marker genes for cortical cell types, all clusters were annotated as EX, IN and non-neuronal cells, the latter being OLI, OPC, AST, MIC, ENDO and PERI ( Figure 2B and Table S3).…”

Section: Linking Chromatin Accessibility To Transcriptome In Differenmentioning

confidence: 99%

“…The cynomolgus monkey (Macaca fascicularis) is one of the most studied non-human primates (NHP) in neuroscience and medicine (6,7). Recent advances in transgenesis and genome-editing technologies have led to successful development of 5 new cynomolgus monkey models to study genetic human neurological disorders (8)(9)(10), making this species an excellent experimental NHP model for brain researchers.…”

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confidence: 99%

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Spatially resolved gene regulatory and disease vulnerability map of the adult Macaque cortex

Lei

Cheng

et al. 2020

Preprint

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Non-human primates (NHP) provide a unique opportunity to study human neurological diseases, yet detailed characterization of the cell types and transcriptional regulatory features in the NHP brain is lacking. We applied a combinatorial indexing assay, sci-ATAC-seq, as well as single-nuclei RNA-seq, to profile chromatin accessibility in 43,793 single cells and transcriptomics in 11,477 cells, respectively, from prefrontal cortex, primary motor cortex and the primary visual cortex of adult cynomolgus monkey Macaca fascularis. Integrative analysis of these two datasets, resolved regulatory elements and transcription factors that specify cell type distinctions, and discovered area-specific diversity in chromatin accessibility and gene expression within excitatory neurons. We also constructed the dynamic landscape of chromatin accessibility and gene expression of oligodendrocyte maturation to characterize adult remyelination. Furthermore, we identified cell type-specific enrichment of differentially spliced gene isoforms and disease-associated single nucleotide polymorphisms. Our datasets permit integrative exploration of complex regulatory dynamics in macaque brain tissue at single-cell resolution.

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Section: Single-cell Chromatin States Define Brain Cortical Cellular mentioning

confidence: 99%

Section: Linking Chromatin Accessibility To Transcriptome In Differenmentioning

confidence: 99%

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confidence: 99%

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Spatially resolved gene regulatory and disease vulnerability map of the adult Macaque cortex

Lei

Cheng

et al. 2020

Preprint

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“…The fact that mosaics are being generated for some models [44,71,75,81] is concerning, as this will certainly influence the results of therapeutic testing. Developing methods to increase the uniformity of in vivo CRISPR-mediated mutagenesis will be helpful [83,84]; otherwise, careful analysis of mutation load and tissue-specific distribution is required in individual animals, perhaps even across generations. Finally, we should understand that each animal system inherently possesses certain fixed limitations (e.g.…”

Section: Discussionmentioning

confidence: 99%

CRISPR-Generated Animal Models of Duchenne Muscular Dystrophy

Lim

Nguyen

Dzierlega

et al. 2020

Preprint

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Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disorder most commonly caused by mutations disrupting the reading frame of the dystrophin (DMD) gene. DMD codes for dystrophin, which is critical for maintaining the integrity of muscle cell membranes. Without dystrophin, muscle cells receive heightened mechanical stress, becoming more susceptible to damage. An active body of research continues to explore therapeutic treatments for DMD as well as to further our understanding of the disease. These efforts rely on having reliable animal models that accurately recapitulate disease presentation in humans. While current animal models of DMD have served this purpose quite well, each comes with their own limitations. To help overcome this, clustered regularly interspaced short palindromic repeats (CRISPR)-based technology has been extremely useful in creating novel animal models for DMD. This review focuses on animal models developed for DMD that have been created using CRISPR, their advantages and disadvantages as well as their applications in the DMD field.

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“…NHPs are obviously close relatives to humans, making them attractive models. However, only a few spontaneous IRDs in primates have been identified [3,4], although steps are being taken to identify more animals with disease-causing mutations and to use genome editing to generate additional models with mutations in genes of importance, either for germline transmission (see [5] for a review) or somatic gene knockout [6]. Another major advantage of large animal models is the presence of a retinal region equivalent to the macula.…”

Section: Introductionmentioning

confidence: 99%

Large Animal Models of Inherited Retinal Degenerations: A Review

Winkler

Occelli

Petersen‐Jones

2020

Cells

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Studies utilizing large animal models of inherited retinal degeneration (IRD) have proven important in not only the development of translational therapeutic approaches, but also in improving our understanding of disease mechanisms. The dog is the predominant species utilized because spontaneous IRD is common in the canine pet population. Cats are also a source of spontaneous IRDs. Other large animal models with spontaneous IRDs include sheep, horses and non-human primates (NHP). The pig has also proven valuable due to the ease in which transgenic animals can be generated and work is ongoing to produce engineered models of other large animal species including NHP. These large animal models offer important advantages over the widely used laboratory rodent models. The globe size and dimensions more closely parallel those of humans and, most importantly, they have a retinal region of high cone density and denser photoreceptor packing for high acuity vision. Laboratory rodents lack such a retinal region and, as macular disease is a critical cause for vision loss in humans, having a comparable retinal region in model species is particularly important. This review will discuss several large animal models which have been used to study disease mechanisms relevant for the equivalent human IRD.

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CRISPR/Cas9-mediated genome editing in nonhuman primates

Cited by 49 publications

References 50 publications

Spatially resolved gene regulatory and disease vulnerability map of the adult Macaque cortex

Spatially resolved gene regulatory and disease vulnerability map of the adult Macaque cortex

CRISPR-Generated Animal Models of Duchenne Muscular Dystrophy

Large Animal Models of Inherited Retinal Degenerations: A Review

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