Highly efficient Cas9-mediated transcriptional programming

Chavez, Alejandro; Scheiman, Jonathan; Vora, Suhani; Pruitt, Benjamin W.; Tuttle, Marcelle; Iyer, Eswar Prasad R.; Lin, Shiquan; Kiani, Samira; Guzman, Christopher D.; Wiegand, Daniel J.; Ter-Ovanesyan, Dmitry; Braff, Jonathan L; Davidsohn, Noah; Housden, Benjamin E.; Perrimon, Norbert; Weiss, Ron; Aach, John; Collins, James J.; Church, George M.

doi:10.1038/nmeth.3312

Cited by 1,273 publications

(1,199 citation statements)

References 22 publications

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“…Significant differences were calculated using a twotailed Student's t-test (** P , 0. Gilbert et al 2014;Chavez et al 2015;Konermann et al 2015;Zhang et al 2015).…”

Section: Resultsmentioning

confidence: 99%

The Chromatin Remodeling Component Arid1a Is a Suppressor of Spontaneous Mammary Tumors in Mice

Kartha¹,

Shen

Maskin³

et al. 2016

Genetics

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Human cancer genome studies have identified the SWI/SNF chromatin remodeling complex member ARID1A as one of the most frequently altered genes in several tumor types. Its role as an ovarian tumor suppressor has been supported in compound knockout mice. Here, we provide genetic and functional evidence that Arid1a is a bona fide mammary tumor suppressor, using the Chromosome aberrations occurring spontaneously 3 (Chaos3) mouse model of sporadic breast cancer. About 70% of mammary tumors that formed in these mice contained a spontaneous deletion removing all or part of one Arid1a allele. Restoration of Arid1a expression in a Chaos3 mammary tumor line with low Arid1a levels greatly impaired its ability to form tumors following injection into cleared mammary glands, indicating that ARID1A insufficiency is crucial for maintenance of these Trp53-proficient tumors. Transcriptome analysis of tumor cells before and after reintroduction of Arid1a expression revealed alterations in growth signaling and cell-cycle checkpoint pathways, in particular the activation of the TRP53 pathway. Consistent with the latter, Arid1a reexpression in tumor cells led to increased p21 (Cdkn1a) expression and dramatic accumulation of cells in G2 phase of the cell cycle. These results not only provide in vivo evidence for a tumor suppressive and/or maintenance role in breast cancer, but also indicate a potential opportunity for therapeutic intervention in ARID1A-deficient human breast cancer subtypes that retain one intact copy of the gene and also maintain wild-type TRP53 activity.

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“…Significant differences were calculated using a twotailed Student's t-test (** P , 0. Gilbert et al 2014;Chavez et al 2015;Konermann et al 2015;Zhang et al 2015).…”

Section: Resultsmentioning

confidence: 99%

The Chromatin Remodeling Component Arid1a Is a Suppressor of Spontaneous Mammary Tumors in Mice

Kartha¹,

Shen

Maskin³

et al. 2016

Genetics

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“…Single dCas9-effector fusions are commonly targeted to adjacent sites using multiple different sgRNAs for maximum impact. In an effort to obtain maximum activation a combination of three different effectors (VP64, p65 and Rta) has been fused in succession to dCas9, resulting in a ~100-fold increase in transactivation of the target genes compared to dCas9-VP64 alone (Chavez et al, 2015). A basic strategy towards achieving temporal control of dCas9-effector target binding is inducible expression of dCas9 or the sgRNA, e.g.…”

Section: Class I -Direct Effector Fusionmentioning

confidence: 99%

dCas9: A Versatile Tool for Epigenome Editing

Brocken¹,

Tark-Dame²,

Dame³

2018

Current Issues in Molecular Biology

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The epigenome is a heritable layer of information not encoded in the DNA sequence of the genome, but in chemical modifications of DNA or histones. These chemical modifications, together with transcription factors, operate as spatiotemporal regulators of genome activity. Dissecting epigenome function requires controlled site-specific alteration of epigenetic information. Such control can be obtained using designed DNA-binding platforms associated with effector domains to function as targeted transcription factors or epigenetic modifiers. Here, we review the use of dCas9 as a novel and versatile tool for fundamental studies on epigenetic landscapes, chromatin structure and transcription regulation, and the potential of this approach in basic research in these fields.

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“…1d, 2b). Likewise, dCas9 can be coupled to activating transcription factor domains, such as the tripartite VP64-p65-Rta (VPR) or the RNAP ω-subunit (rpoZ), which have been characterized as powerful tools for activating genes [4,7,44,91] (Fig. 1d).…”

Section: Expanding Cas9 Features Through Enzyme Engineeringmentioning

confidence: 99%

Advancing biotechnology with CRISPR/Cas9: recent applications and patent landscape

Ferreira

David

Nielsen

2018

Journal of Industrial Microbiology and Biotechnology

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Clustered regularly interspaced short palindromic repeats (CRISPR) is poised to become one of the key scientific discoveries of the twenty-first century. Originating from prokaryotic and archaeal immune systems to counter phage invasions, CRISPRbased applications have been tailored for manipulating a broad range of living organisms. From the different elucidated types of CRISPR mechanisms, the type II system adapted from Streptococcus pyogenes has been the most exploited as a tool for genome engineering and gene regulation. In this review, we describe the different applications of CRISPR/Cas9 technology in the industrial biotechnology field. Next, we detail the current status of the patent landscape, highlighting its exploitation through different companies, and conclude with future perspectives of this technology.

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Highly efficient Cas9-mediated transcriptional programming

Cited by 1,273 publications

References 22 publications

The Chromatin Remodeling Component Arid1a Is a Suppressor of Spontaneous Mammary Tumors in Mice

The Chromatin Remodeling Component Arid1a Is a Suppressor of Spontaneous Mammary Tumors in Mice

dCas9: A Versatile Tool for Epigenome Editing

Advancing biotechnology with CRISPR/Cas9: recent applications and patent landscape

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