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  1. Article ; Online: An Engineered Synthetic Receptor-Aptamer Pair for an Artificial Signal Transduction System.

    Liu, Hanrui / Baeumler, Toni A / Nakamura, Kai / Okada, Yuga / Cho, Seojung / Eguchi, Akihiro / Kuroda, Daisuke / Tsumoto, Kouhei / Ueki, Ryosuke / Sando, Shinsuke

    ACS nano

    2023  Volume 17, Issue 10, Page(s) 9039–9048

    Abstract: Cell membrane receptors regulate cellular responses through sensing extracellular environmental signals and subsequently transducing them. Receptor engineering provides a means of directing cells to react to a designated external cue and exert programmed ...

    Abstract Cell membrane receptors regulate cellular responses through sensing extracellular environmental signals and subsequently transducing them. Receptor engineering provides a means of directing cells to react to a designated external cue and exert programmed functions. However, rational design and precise modulation of receptor signaling activity remain challenging. Here, we report an aptamer-based signal transduction system and its applications in controlling and customizing the functions of engineered receptors. A previously reported membrane receptor-aptamer pair was used to design a synthetic receptor system that transduces cell signaling depending on exogenous aptamer input. To eliminate the cross-reactivity of the receptor with its native ligand, the extracellular domain of the receptor was engineered to ensure that the receptor was solely activated by the DNA aptamer. The present system features tunability in the signaling output level using aptamer ligands with different receptor dimerization propensities. In addition, the functional programmability of DNA aptamers enables the modular sensing of extracellular molecules without the need for genetic engineering of the receptor.
    MeSH term(s) Receptors, Artificial ; Aptamers, Nucleotide/genetics ; Receptors, Cell Surface ; Ligands ; Signal Transduction/physiology
    Chemical Substances Receptors, Artificial ; Aptamers, Nucleotide ; Receptors, Cell Surface ; Ligands
    Language English
    Publishing date 2023-05-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1936-086X
    ISSN (online) 1936-086X
    DOI 10.1021/acsnano.2c11744
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Engineering Synthetic Signaling Pathways with Programmable dCas9-Based Chimeric Receptors.

    Baeumler, Toni A / Ahmed, Ahmed Ashour / Fulga, Tudor A

    Cell reports

    2017  Volume 20, Issue 11, Page(s) 2639–2653

    Abstract: Synthetic receptors provide a powerful experimental tool for generation of designer cells capable of monitoring the environment, sensing specific input signals, and executing diverse custom response programs. To advance the promise of cellular ... ...

    Abstract Synthetic receptors provide a powerful experimental tool for generation of designer cells capable of monitoring the environment, sensing specific input signals, and executing diverse custom response programs. To advance the promise of cellular engineering, we have developed a class of chimeric receptors that integrate a highly programmable and portable nuclease-deficient CRISPR/Cas9 (dCas9) signal transduction module. We demonstrate that the core dCas9 synthetic receptor (dCas9-synR) architecture can be readily adapted to various classes of native ectodomain scaffolds, linking their natural inputs with orthogonal output functions. Importantly, these receptors achieved stringent OFF/ON state transition characteristics, showed agonist-mediated dose-dependent activation, and could be programmed to couple specific disease markers with diverse, therapeutically relevant multi-gene expression circuits. The modular dCas9-synR platform developed here provides a generalizable blueprint for designing next generations of synthetic receptors, which will enable the implementation of highly complex combinatorial functions in cellular engineering.
    MeSH term(s) CRISPR-Cas Systems/genetics ; Cell Membrane/metabolism ; Gene Expression ; Genetic Engineering ; HEK293 Cells ; Humans ; Models, Biological ; Peptide Hydrolases/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Recombinant Proteins/metabolism ; Signal Transduction ; Transcription Factors/metabolism ; Transcriptional Activation/genetics
    Chemical Substances Receptors, G-Protein-Coupled ; Recombinant Proteins ; Transcription Factors ; Peptide Hydrolases (EC 3.4.-)
    Language English
    Publishing date 2017-09-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2649101-1
    ISSN 2211-1247 ; 2211-1247
    ISSN (online) 2211-1247
    ISSN 2211-1247
    DOI 10.1016/j.celrep.2017.08.044
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Engineering Synthetic Signaling Pathways with Programmable dCas9-Based Chimeric Receptors

    Toni A. Baeumler / Ahmed Ashour Ahmed / Tudor A. Fulga

    Cell Reports, Vol 20, Iss 11, Pp 2639-

    2017  Volume 2653

    Abstract: Synthetic receptors provide a powerful experimental tool for generation of designer cells capable of monitoring the environment, sensing specific input signals, and executing diverse custom response programs. To advance the promise of cellular ... ...

    Abstract Synthetic receptors provide a powerful experimental tool for generation of designer cells capable of monitoring the environment, sensing specific input signals, and executing diverse custom response programs. To advance the promise of cellular engineering, we have developed a class of chimeric receptors that integrate a highly programmable and portable nuclease-deficient CRISPR/Cas9 (dCas9) signal transduction module. We demonstrate that the core dCas9 synthetic receptor (dCas9-synR) architecture can be readily adapted to various classes of native ectodomain scaffolds, linking their natural inputs with orthogonal output functions. Importantly, these receptors achieved stringent OFF/ON state transition characteristics, showed agonist-mediated dose-dependent activation, and could be programmed to couple specific disease markers with diverse, therapeutically relevant multi-gene expression circuits. The modular dCas9-synR platform developed here provides a generalizable blueprint for designing next generations of synthetic receptors, which will enable the implementation of highly complex combinatorial functions in cellular engineering.
    Keywords synthetic receptors ; chimeric receptors ; CRISPR ; dCas9-VP64 ; split Cas9 ; GPCR ; RTK ; genome engineering ; dCas9-synR ; transcriptional programs ; Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2017-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Addendum: Precise tuning of gene expression levels in mammalian cells.

    Michaels, Yale S / Barnkob, Mike B / Barbosa, Hector / Baeumler, Toni A / Thompson, Mary K / Andre, Violaine / Colin-York, Huw / Fritzsche, Marco / Gileadi, Uzi / Sheppard, Hilary M / Knapp, David J H F / Milne, Thomas A / Cerundolo, Vincenzo / Fulga, Tudor A

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 2622

    Abstract: Following re-sequencing of the miSFIT constructs used in the paper, two of the construct variants inserted into the 3'UTR of PD-1, namely '12C' and '17A, 18G', have been found to contain additional insertions not present in the other construct variants. ... ...

    Abstract Following re-sequencing of the miSFIT constructs used in the paper, two of the construct variants inserted into the 3'UTR of PD-1, namely '12C' and '17A, 18G', have been found to contain additional insertions not present in the other construct variants. The data points corresponding to these constructs in Figs. 2c, f and Supplementary Fig. 9 are therefore no longer valid. However the overall conclusion that step-wise control over gene expression levels using the miSFIT constructs remains unaffected by these errors. Updated versions of Fig. 2 and Supplementary Fig. 9 are presented in the accompanying Addendum.
    Language English
    Publishing date 2019-06-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-10615-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Author Correction: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease.

    Serra, Eva Gonçalves / Schwerd, Tobias / Moutsianas, Loukas / Cavounidis, Athena / Fachal, Laura / Pandey, Sumeet / Kammermeier, Jochen / Croft, Nicholas M / Posovszky, Carsten / Rodrigues, Astor / Russell, Richard K / Barakat, Farah / Auth, Marcus K H / Heuschkel, Robert / Zilbauer, Matthias / Fyderek, Krzysztof / Braegger, Christian / Travis, Simon P / Satsangi, Jack /
    Parkes, Miles / Thapar, Nikhil / Ferry, Helen / Matte, Julie C / Gilmour, Kimberly C / Wedrychowicz, Andrzej / Sullivan, Peter / Moore, Carmel / Sambrook, Jennifer / Ouwehand, Willem / Roberts, David / Danesh, John / Baeumler, Toni A / Fulga, Tudor A / Carrami, Eli M / Ahmed, Ahmed / Wilson, Rachel / Barrett, Jeffrey C / Elkadri, Abdul / Griffiths, Anne M / Snapper, Scott B / Shah, Neil / Muise, Aleixo M / Wilson, David C / Uhlig, Holm H / Anderson, Carl A

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 3576

    Language English
    Publishing date 2022-06-22
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-31010-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Precise tuning of gene expression levels in mammalian cells.

    Michaels, Yale S / Barnkob, Mike B / Barbosa, Hector / Baeumler, Toni A / Thompson, Mary K / Andre, Violaine / Colin-York, Huw / Fritzsche, Marco / Gileadi, Uzi / Sheppard, Hilary M / Knapp, David J H F / Milne, Thomas A / Cerundolo, Vincenzo / Fulga, Tudor A

    Nature communications

    2019  Volume 10, Issue 1, Page(s) 818

    Abstract: Precise, analogue regulation of gene expression is critical for cellular function in mammals. In contrast, widely employed experimental and therapeutic approaches such as knock-in/out strategies are more suitable for binary control of gene activity. Here ...

    Abstract Precise, analogue regulation of gene expression is critical for cellular function in mammals. In contrast, widely employed experimental and therapeutic approaches such as knock-in/out strategies are more suitable for binary control of gene activity. Here we report on a method for precise control of gene expression levels in mammalian cells using engineered microRNA response elements (MREs). First, we measure the efficacy of thousands of synthetic MRE variants under the control of an endogenous microRNA by high-throughput sequencing. Guided by this data, we establish a library of microRNA silencing-mediated fine-tuners (miSFITs) of varying strength that can be employed to precisely control the expression of user-specified genes. We apply this technology to tune the T-cell co-inhibitory receptor PD-1 and to explore how antigen expression influences T-cell activation and tumour growth. Finally, we employ CRISPR/Cas9 mediated homology directed repair to introduce miSFITs into the BRCA1 3'UTR, demonstrating that this versatile tool can be used to tune endogenous genes.
    MeSH term(s) 3' Untranslated Regions ; Animals ; B7-H1 Antigen/genetics ; CRISPR-Cas Systems ; Gene Expression Regulation/genetics ; Genes, BRCA1 ; Genetic Techniques ; HEK293 Cells ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Melanoma, Experimental/genetics ; Melanoma, Experimental/pathology ; Mice, Inbred C57BL ; MicroRNAs/genetics ; Ovalbumin/genetics ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Response Elements ; Xenograft Model Antitumor Assays
    Chemical Substances 3' Untranslated Regions ; B7-H1 Antigen ; CD274 protein, human ; MicroRNAs ; Recombinant Proteins ; Ovalbumin (9006-59-1)
    Language English
    Publishing date 2019-02-18
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-019-08777-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Precise tuning of gene expression levels in mammalian cells

    Yale S. Michaels / Mike B. Barnkob / Hector Barbosa / Toni A. Baeumler / Mary K. Thompson / Violaine Andre / Huw Colin-York / Marco Fritzsche / Uzi Gileadi / Hilary M. Sheppard / David J. H. F. Knapp / Thomas A. Milne / Vincenzo Cerundolo / Tudor A. Fulga

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 12

    Abstract: Analogue regulation of gene expression is important for normal function in mammals but existing genetic technologies are designed to achieve ON/OFF control. Here the authors develop synthetic microRNA silencing-mediated fine-tuners (miSFITs) to precisely ...

    Abstract Analogue regulation of gene expression is important for normal function in mammals but existing genetic technologies are designed to achieve ON/OFF control. Here the authors develop synthetic microRNA silencing-mediated fine-tuners (miSFITs) to precisely control target gene expression levels.
    Keywords Science ; Q
    Language English
    Publishing date 2019-02-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Precise tuning of gene expression levels in mammalian cells

    Yale S. Michaels / Mike B. Barnkob / Hector Barbosa / Toni A. Baeumler / Mary K. Thompson / Violaine Andre / Huw Colin-York / Marco Fritzsche / Uzi Gileadi / Hilary M. Sheppard / David J. H. F. Knapp / Thomas A. Milne / Vincenzo Cerundolo / Tudor A. Fulga

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 12

    Abstract: Analogue regulation of gene expression is important for normal function in mammals but existing genetic technologies are designed to achieve ON/OFF control. Here the authors develop synthetic microRNA silencing-mediated fine-tuners (miSFITs) to precisely ...

    Abstract Analogue regulation of gene expression is important for normal function in mammals but existing genetic technologies are designed to achieve ON/OFF control. Here the authors develop synthetic microRNA silencing-mediated fine-tuners (miSFITs) to precisely control target gene expression levels.
    Keywords Science ; Q
    Language English
    Publishing date 2019-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Addendum

    Yale S. Michaels / Mike B. Barnkob / Hector Barbosa / Toni A. Baeumler / Mary K. Thompson / Violaine Andre / Huw Colin-York / Marco Fritzsche / Uzi Gileadi / Hilary M. Sheppard / David J. H. F. Knapp / Thomas A. Milne / Vincenzo Cerundolo / Tudor A. Fulga

    Nature Communications, Vol 10, Iss 1, Pp 1-

    Precise tuning of gene expression levels in mammalian cells

    2019  Volume 3

    Abstract: Following re-sequencing of the miSFIT constructs used in the paper, two of the construct variants inserted into the 3’UTR of PD-1, namely ‘12C’ and ‘17A, 18G’, have been found to contain additional insertions not present in the other construct variants. ... ...

    Abstract Following re-sequencing of the miSFIT constructs used in the paper, two of the construct variants inserted into the 3’UTR of PD-1, namely ‘12C’ and ‘17A, 18G’, have been found to contain additional insertions not present in the other construct variants. The data points corresponding to these constructs in Figs. 2c, f and Supplementary Fig. 9 are therefore no longer valid. However the overall conclusion that step-wise control over gene expression levels using the miSFIT constructs remains unaffected by these errors. Updated versions of Fig. 2 and Supplementary Fig. 9 are presented in the accompanying Addendum.
    Keywords Science ; Q
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Addendum

    Yale S. Michaels / Mike B. Barnkob / Hector Barbosa / Toni A. Baeumler / Mary K. Thompson / Violaine Andre / Huw Colin-York / Marco Fritzsche / Uzi Gileadi / Hilary M. Sheppard / David J. H. F. Knapp / Thomas A. Milne / Vincenzo Cerundolo / Tudor A. Fulga

    Nature Communications, Vol 10, Iss 1, Pp 1-

    Precise tuning of gene expression levels in mammalian cells

    2019  Volume 3

    Abstract: Following re-sequencing of the miSFIT constructs used in the paper, two of the construct variants inserted into the 3’UTR of PD-1, namely ‘12C’ and ‘17A, 18G’, have been found to contain additional insertions not present in the other construct variants. ... ...

    Abstract Following re-sequencing of the miSFIT constructs used in the paper, two of the construct variants inserted into the 3’UTR of PD-1, namely ‘12C’ and ‘17A, 18G’, have been found to contain additional insertions not present in the other construct variants. The data points corresponding to these constructs in Figs. 2c, f and Supplementary Fig. 9 are therefore no longer valid. However the overall conclusion that step-wise control over gene expression levels using the miSFIT constructs remains unaffected by these errors. Updated versions of Fig. 2 and Supplementary Fig. 9 are presented in the accompanying Addendum.
    Keywords Science ; Q
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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