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Article ; Online: A multiplexed, automated evolution pipeline enables scalable discovery and characterization of biosensors

Brent Townshend / Joy S. Xiang / Gabriel Manzanarez / Eric J. Hayden / Christina D. Smolke

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 15

Abstract: Biosensors are key to engineered biological systems. Here the authors demonstrate rapid de novo in vitro evolution of RNA biosensors of small molecules in a fully automated system. ...

Abstract	Biosensors are key to engineered biological systems. Here the authors demonstrate rapid de novo in vitro evolution of RNA biosensors of small molecules in a fully automated system.
Keywords	Science ; Q
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A multiplexed, automated evolution pipeline enables scalable discovery and characterization of biosensors.

Townshend, Brent / Xiang, Joy S / Manzanarez, Gabriel / Hayden, Eric J / Smolke, Christina D

Nature communications

2021 Volume 12, Issue 1, Page(s) 1437

Abstract: Biosensors are key components in engineered biological systems, providing a means of measuring and acting upon the large biochemical space in living cells. However, generating small molecule sensing elements and integrating them into in vivo biosensors ... ...

Abstract	Biosensors are key components in engineered biological systems, providing a means of measuring and acting upon the large biochemical space in living cells. However, generating small molecule sensing elements and integrating them into in vivo biosensors have been challenging. Here, using aptamer-coupled ribozyme libraries and a ribozyme regeneration method, de novo rapid in vitro evolution of RNA biosensors (DRIVER) enables multiplexed discovery of biosensors. With DRIVER and high-throughput characterization (CleaveSeq) fully automated on liquid-handling systems, we identify and validate biosensors against six small molecules, including five for which no aptamers were previously found. DRIVER-evolved biosensors are applied directly to regulate gene expression in yeast, displaying activation ratios up to 33-fold. DRIVER biosensors are also applied in detecting metabolite production from a multi-enzyme biosynthetic pathway. This work demonstrates DRIVER as a scalable pipeline for engineering de novo biosensors with wide-ranging applications in biomanufacturing, diagnostics, therapeutics, and synthetic biology.
MeSH term(s)	Aptamers, Nucleotide/chemistry ; Biosensing Techniques/methods ; Gene Expression/genetics ; Green Fluorescent Proteins/metabolism ; Metabolic Engineering/methods ; RNA, Catalytic/chemistry ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Synthetic Biology/methods
Chemical Substances	Aptamers, Nucleotide ; RNA, Catalytic ; Green Fluorescent Proteins (147336-22-9)
Language	English
Publishing date	2021-03-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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/s41467-021-21716-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: HydRA: Deep-learning models for predicting RNA-binding capacity from protein interaction association context and protein sequence.

Jin, Wenhao / Brannan, Kristopher W / Kapeli, Katannya / Park, Samuel S / Tan, Hui Qing / Gosztyla, Maya L / Mujumdar, Mayuresh / Ahdout, Joshua / Henroid, Bryce / Rothamel, Katherine / Xiang, Joy S / Wong, Limsoon / Yeo, Gene W

Molecular cell

2023 Volume 83, Issue 14, Page(s) 2595–2611.e11

Abstract: RNA-binding proteins (RBPs) control RNA metabolism to orchestrate gene expression and, when dysfunctional, underlie human diseases. Proteome-wide discovery efforts predict thousands of RBP candidates, many of which lack canonical RNA-binding domains ( ... ...

Abstract	RNA-binding proteins (RBPs) control RNA metabolism to orchestrate gene expression and, when dysfunctional, underlie human diseases. Proteome-wide discovery efforts predict thousands of RBP candidates, many of which lack canonical RNA-binding domains (RBDs). Here, we present a hybrid ensemble RBP classifier (HydRA), which leverages information from both intermolecular protein interactions and internal protein sequence patterns to predict RNA-binding capacity with unparalleled specificity and sensitivity using support vector machines (SVMs), convolutional neural networks (CNNs), and Transformer-based protein language models. Occlusion mapping by HydRA robustly detects known RBDs and predicts hundreds of uncharacterized RNA-binding associated domains. Enhanced CLIP (eCLIP) for HydRA-predicted RBP candidates reveals transcriptome-wide RNA targets and confirms RNA-binding activity for HydRA-predicted RNA-binding associated domains. HydRA accelerates construction of a comprehensive RBP catalog and expands the diversity of RNA-binding associated domains.
MeSH term(s)	Animals ; Humans ; RNA/metabolism ; Protein Binding ; Binding Sites/genetics ; Hydra/genetics ; Hydra/metabolism ; Deep Learning
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2023-07-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.06.019
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Article ; Online: HydRA: Deep-learning models for predicting RNA-binding capacity from protein interaction association context and protein sequence

Jin, Wenhao / Brannan, Kristopher W. / Kapeli, Katannya / Park, Samuel S. / Tan, Hui Qing / Gosztyla, Maya L. / Mujumdar, Mayuresh / Ahdout, Joshua / Henroid, Bryce / Rothamel, Katherine / Xiang, Joy S. / Wong, Limsoon / Yeo, Gene W.

Molecular Cell. 20232023 July 07, July 07, v. 83, no. 14 p.2595-2611.e11

2023

Abstract	RNA-binding proteins (RBPs) control RNA metabolism to orchestrate gene expression and, when dysfunctional, underlie human diseases. Proteome-wide discovery efforts predict thousands of RBP candidates, many of which lack canonical RNA-binding domains (RBDs). Here, we present a hybrid ensemble RBP classifier (HydRA), which leverages information from both intermolecular protein interactions and internal protein sequence patterns to predict RNA-binding capacity with unparalleled specificity and sensitivity using support vector machines (SVMs), convolutional neural networks (CNNs), and Transformer-based protein language models. Occlusion mapping by HydRA robustly detects known RBDs and predicts hundreds of uncharacterized RNA-binding associated domains. Enhanced CLIP (eCLIP) for HydRA-predicted RBP candidates reveals transcriptome-wide RNA targets and confirms RNA-binding activity for HydRA-predicted RNA-binding associated domains. HydRA accelerates construction of a comprehensive RBP catalog and expands the diversity of RNA-binding associated domains.
Keywords	Hydra ; RNA ; amino acid sequences ; gene expression ; humans ; metabolism ; support vector machines ; RNA-binding proteins ; machine learning ; RNA-binding domains ; protein-protein interaction network
Language	English
Dates of publication	2023-0707
Size	p. 2595-2611.e11.
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.06.019
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Article ; Online: Mammalian synthetic biology for studying the cell.

Mathur, Melina / Xiang, Joy S / Smolke, Christina D

The Journal of cell biology

2016 Volume 216, Issue 1, Page(s) 73–82

Abstract: Synthetic biology is advancing the design of genetic devices that enable the study of cellular and molecular biology in mammalian cells. These genetic devices use diverse regulatory mechanisms to both examine cellular processes and achieve precise and ... ...

Abstract	Synthetic biology is advancing the design of genetic devices that enable the study of cellular and molecular biology in mammalian cells. These genetic devices use diverse regulatory mechanisms to both examine cellular processes and achieve precise and dynamic control of cellular phenotype. Synthetic biology tools provide novel functionality to complement the examination of natural cell systems, including engineered molecules with specific activities and model systems that mimic complex regulatory processes. Continued development of quantitative standards and computational tools will expand capacities to probe cellular mechanisms with genetic devices to achieve a more comprehensive understanding of the cell. In this study, we review synthetic biology tools that are being applied to effectively investigate diverse cellular processes, regulatory networks, and multicellular interactions. We also discuss current challenges and future developments in the field that may transform the types of investigation possible in cell biology.
MeSH term(s)	Alternative Splicing ; Cell Biology ; Cell Communication ; Cytological Techniques ; Epigenesis, Genetic ; Gene Regulatory Networks ; Humans ; Male ; RNA Interference ; Signal Transduction ; Synthetic Biology/methods
Language	English
Publishing date	2016-12-08
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201611002
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Article ; Online: Massively parallel RNA device engineering in mammalian cells with RNA-Seq.

Xiang, Joy S / Kaplan, Matias / Dykstra, Peter / Hinks, Michaela / McKeague, Maureen / Smolke, Christina D

Nature communications

2019 Volume 10, Issue 1, Page(s) 4327

Abstract: Synthetic RNA-based genetic devices dynamically control a wide range of gene-regulatory processes across diverse cell types. However, the limited throughput of quantitative assays in mammalian cells has hindered fast iteration and interrogation of ... ...

Abstract	Synthetic RNA-based genetic devices dynamically control a wide range of gene-regulatory processes across diverse cell types. However, the limited throughput of quantitative assays in mammalian cells has hindered fast iteration and interrogation of sequence space needed to identify new RNA devices. Here we report developing a quantitative, rapid and high-throughput mammalian cell-based RNA-Seq assay to efficiently engineer RNA devices. We identify new ribozyme-based RNA devices that respond to theophylline, hypoxanthine, cyclic-di-GMP, and folinic acid from libraries of ~22,700 sequences in total. The small molecule responsive devices exhibit low basal expression and high activation ratios, significantly expanding our toolset of highly functional ribozyme switches. The large datasets obtained further provide conserved sequence and structure motifs that may be used for rationally guided design. The RNA-Seq approach offers a generally applicable strategy for developing broad classes of RNA devices, thereby advancing the engineering of genetic devices for mammalian systems.
MeSH term(s)	Animals ; Gene Regulatory Networks ; Genetic Engineering ; HEK293 Cells ; Humans ; Mammals/genetics ; Nucleotide Motifs ; RNA, Catalytic/chemistry ; RNA, Catalytic/metabolism ; RNA, Catalytic/physiology ; RNA-Seq/methods ; Synthetic Biology/methods
Chemical Substances	RNA, Catalytic
Language	English
Publishing date	2019-09-23
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/s41467-019-12334-y
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Massively parallel RNA device engineering in mammalian cells with RNA-Seq

Joy S. Xiang / Matias Kaplan / Peter Dykstra / Michaela Hinks / Maureen McKeague / Christina D. Smolke

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

2019 Volume 16

Abstract: Synthetic RNA-based devices can dynamically control a wide range of processes. Here the authors develop a quantitative and high-throughput mammalian cell-based RNA-seq assay to efficiently engineer ribozyme switches. ...

Abstract	Synthetic RNA-based devices can dynamically control a wide range of processes. Here the authors develop a quantitative and high-throughput mammalian cell-based RNA-seq assay to efficiently engineer ribozyme switches.
Keywords	Science ; Q
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Massively parallel RNA device engineering in mammalian cells with RNA-Seq

Joy S. Xiang / Matias Kaplan / Peter Dykstra / Michaela Hinks / Maureen McKeague / Christina D. Smolke

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

2019 Volume 16

Abstract	Synthetic RNA-based devices can dynamically control a wide range of processes. Here the authors develop a quantitative and high-throughput mammalian cell-based RNA-seq assay to efficiently engineer ribozyme switches.
Keywords	Science ; Q
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: High-throughput cellular RNA device engineering.

Townshend, Brent / Kennedy, Andrew B / Xiang, Joy S / Smolke, Christina D

Nature methods

2015 Volume 12, Issue 10, Page(s) 989–994

Abstract: Methods for rapidly assessing sequence-structure-function landscapes and developing conditional gene-regulatory devices are critical to our ability to manipulate and interface with biology. We describe a framework for engineering RNA devices from ... ...

Abstract	Methods for rapidly assessing sequence-structure-function landscapes and developing conditional gene-regulatory devices are critical to our ability to manipulate and interface with biology. We describe a framework for engineering RNA devices from preexisting aptamers that exhibit ligand-responsive ribozyme tertiary interactions. Our methodology utilizes cell sorting, high-throughput sequencing and statistical data analyses to enable parallel measurements of the activities of hundreds of thousands of sequences from RNA device libraries in the absence and presence of ligands. Our tertiary-interaction RNA devices performed better in terms of gene silencing, activation ratio and ligand sensitivity than optimized RNA devices that rely on secondary-structure changes. We applied our method to build biosensors for diverse ligands and determine consensus sequences that enable ligand-responsive tertiary interactions. These methods advance our ability to develop broadly applicable genetic tools and to elucidate the underlying sequence-structure-function relationships that empower rational design of complex biomolecules.
MeSH term(s)	Aptamers, Nucleotide/chemistry ; Aptamers, Nucleotide/metabolism ; Biosensing Techniques ; Data Interpretation, Statistical ; Flow Cytometry/methods ; Gene Expression Regulation/drug effects ; Gene Library ; Genetic Engineering/methods ; Green Fluorescent Proteins/genetics ; High-Throughput Nucleotide Sequencing/methods ; Ligands ; Nepovirus/genetics ; RNA, Catalytic/chemistry ; Riboswitch/genetics ; Surface Plasmon Resonance ; Theophylline/metabolism ; Theophylline/pharmacology
Chemical Substances	Aptamers, Nucleotide ; Ligands ; RNA, Catalytic ; Riboswitch ; Green Fluorescent Proteins (147336-22-9) ; Theophylline (C137DTR5RG)
Language	English
Publishing date	2015-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2169522-2
ISSN	1548-7105 ; 1548-7091
ISSN (online)	1548-7105
ISSN	1548-7091
DOI	10.1038/nmeth.3486
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Article ; Online: A novel molecular rotor facilitates detection of p53-DNA interactions using the Fluorescent Intercalator Displacement Assay

Walter L. Goh / Min Yen Lee / Ting Xiang Lim / Joy S. Chua / Sydney Brenner / Farid J. Ghadessy / Yin Nah Teo

Scientific Reports, Vol 8, Iss 1, Pp 1-

2018 Volume 13

Abstract: Abstract We have investigated the use of fluorescent molecular rotors as probes for detection of p53 binding to DNA. These are a class of fluorophores that undergo twisted intramolecular charge transfer (TICT). They are non-fluorescent in a freely ... ...

Abstract	Abstract We have investigated the use of fluorescent molecular rotors as probes for detection of p53 binding to DNA. These are a class of fluorophores that undergo twisted intramolecular charge transfer (TICT). They are non-fluorescent in a freely rotating conformation and experience a fluorescence increase when restricted in the planar conformation. We hypothesized that intercalation of a molecular rotor between DNA base pairs would result in a fluorescence turn-on signal. Upon displacement by a DNA binding protein, measurable loss of signal would facilitate use of the molecular rotor in the fluorescent intercalator displacement (FID) assay. A panel of probes was interrogated using the well-established p53 model system across various DNA response elements. A novel, readily synthesizable molecular rotor incorporating an acridine orange DNA intercalating group (AO-R) outperformed other conventional dyes in the FID assay. It enabled relative measurement of p53 sequence-specific DNA interactions and study of the dominant-negative effects of cancer-associated p53 mutants. In a further application, AO-R also proved useful for staining apoptotic cells in live zebrafish embryos.
Keywords	Medicine ; R ; Science ; Q
Subject code	500
Language	English
Publishing date	2018-08-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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