Chemogenetic control of gene expression and cell signaling with antiviral drugs

Tague, Elliot P.; Dotson, Hannah L.; Tunney, Shannon N.; Sloas, D. Christopher; Ngo, John T.

doi:10.1038/s41592-018-0042-y

Cited by 50 publications

(47 citation statements)

References 25 publications

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“…The availability of ANR to basally localize a protein activity fused to NS3a away from a site of action, or to act as an intramolecular regulatory switch, provides an appealing option for reducing background, but protease-based NS3a control systems offer the possibility of obtaining the complete absence of a protein activity in the cell prior to the addition of a small molecule input. 10,11,27,42 However, the reduced background that can be obtained with protease-based systems comes at the expense of speed, as protein accumulation is required for activation. Furthermore, we have found that catalytically-dead NS3a is an equally effective component of PROCISiR as the active protease, which is advantageous for applications in which off-target proteolytic activity may be a concern.…”

Section: Discussionmentioning

confidence: 99%

Multi-input chemical control of protein dimerization for programming graded cellular responses

et al. 2019

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Chemical and optogenetic methods for post-translationally controlling protein function have enabled new discoveries and the engineering of synthetic cellular functions. However, most of these methods only confer single-input, single-output control. To increase the diversity of posttranslational behaviors that can be programmed we built a system based on a single protein receiver that can integrate multiple drug inputs, including approved therapeutics. Our system translates drug inputs into diverse outputs with engineered reader proteins that provide variable dimerization states of the receiver protein. We show that our single receiver protein architecture can be used to program diverse cellular responses, including graded and proportional dual-output control of transcription and mammalian cell signaling. We apply our tools to titrate the competing activities of the Rac and Rho GTPases to control cell morphology. Our receiver protein and suite Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Section: Discussionmentioning

confidence: 99%

Multi-input chemical control of protein dimerization for programming graded cellular responses

et al. 2019

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“…The protease domain connects dCas9 and the effector, the linker is cleaved unless the NS3 inhibitor is present. The inhibitor binds the NS3 domain and prevents separation of dCas9 from the effector ( Figure 3D) [102]. A similar system takes advantage of proteasomal degradation, ligand-(Z)-4-hydroxytamoxifen (4OHT) binds a destabilized domain of the estrogen receptor fused to the effector domain and stabilizes it.…”

Section: Inducible Systemsmentioning

confidence: 99%

CRISPR/Cas9 Epigenome Editing Potential for Rare Imprinting Diseases: A Review

Syding

Nickl

Kašpárek

et al. 2020

Cells

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Imprinting diseases (IDs) are rare congenital disorders caused by aberrant dosages of imprinted genes. Rare IDs are comprised by a group of several distinct disorders that share a great deal of homology in terms of genetic etiologies and symptoms. Disruption of genetic or epigenetic mechanisms can cause issues with regulating the expression of imprinted genes, thus leading to disease. Genetic mutations affect the imprinted genes, duplications, deletions, and uniparental disomy (UPD) are reoccurring phenomena causing imprinting diseases. Epigenetic alterations on methylation marks in imprinting control centers (ICRs) also alters the expression patterns and the majority of patients with rare IDs carries intact but either silenced or overexpressed imprinted genes. Canonical CRISPR/Cas9 editing relying on double-stranded DNA break repair has little to offer in terms of therapeutics for rare IDs. Instead CRISPR/Cas9 can be used in a more sophisticated way by targeting the epigenome. Catalytically dead Cas9 (dCas9) tethered with effector enzymes such as DNA de- and methyltransferases and histone code editors in addition to systems such as CRISPRa and CRISPRi have been shown to have high epigenome editing efficiency in eukaryotic cells. This new era of CRISPR epigenome editors could arguably be a game-changer for curing and treating rare IDs by refined activation and silencing of disturbed imprinted gene expression. This review describes major CRISPR-based epigenome editors and points out their potential use in research and therapy of rare imprinting diseases.

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“…Inserted between dCas9 domain and the effector domain, NS3 promoted the cleavage between these two domains, unless an antiviral NS3 inhibitor BLIN-2061 was present, which inhibited NS3 activity and maintain the full length of the functional dCas9 fusion protein (Figure 5d). Using this system, the activity of dCas9-NS3-VPR can be controlled by BLIN-2061 in dosage-dependent and reversible manners to regulate CXCR4 expression [126].…”

Section: Other Inducible Approaches Applicable To Epigenome Editingmentioning

confidence: 99%

Chemical and Light Inducible Epigenome Editing

Zhao

Wang

Liang

2020

IJMS

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The epigenome defines the unique gene expression patterns and resulting cellular behaviors in different cell types. Epigenome dysregulation has been directly linked to various human diseases. Epigenome editing enabling genome locus-specific targeting of epigenome modifiers to directly alter specific local epigenome modifications offers a revolutionary tool for mechanistic studies in epigenome regulation as well as the development of novel epigenome therapies. Inducible and reversible epigenome editing provides unique temporal control critical for understanding the dynamics and kinetics of epigenome regulation. This review summarizes the progress in the development of spatiotemporal-specific tools using small molecules or light as inducers to achieve the conditional control of epigenome editing and their applications in epigenetic research.

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Chemogenetic control of gene expression and cell signaling with antiviral drugs

Cited by 50 publications

References 25 publications

Multi-input chemical control of protein dimerization for programming graded cellular responses

Multi-input chemical control of protein dimerization for programming graded cellular responses

CRISPR/Cas9 Epigenome Editing Potential for Rare Imprinting Diseases: A Review

Chemical and Light Inducible Epigenome Editing

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