Modular construction of mammalian gene circuits using TALE transcriptional repressors

Li, Yinqing; Jiang, Yuliang; Chen, He; Liao, Weixi; Li, Zhihua; Weiss, Ron; Xie, Zhen

doi:10.1038/nchembio.1736

Cited by 80 publications

(101 citation statements)

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“…Localizing a DBD without an effector domain to promoter regions or downstream of the transcription start site can silence gene expression 32, 37, 68, 69 . In these strategies, repression is caused by steric interference of transcription factor binding and RNA polymerase elongation 69 .…”

Section: Site-specific Epigenome Editingmentioning

confidence: 99%

Editing the epigenome: technologies for programmable transcription and epigenetic modulation

et al. 2016

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Gene regulation is a highly complex and tightly controlled process that defines cell identity, health, and response to environmental signals. Technologies for precisely perturbing gene regulation are critical for improving our understanding of its coordination and for manipulating pathways for applications in biotechnology and medicine. Recently developed DNA-targeting platforms, including zinc finger proteins, TALEs, and CRISPR/Cas9, have enabled the recruitment of transcriptional modulators and epigenome-modifying factors to any genomic site. These technologies are generating novel insights into the function of epigenetic marks and the role of genome structure in gene expression. Additionally, custom transcriptional and epigenetic regulation is facilitating refined control over cell function and decision-making. The unique properties of the CRISPR/Cas9 system have also created new opportunities for multiplexing targets and manipulating complex gene expression patterns, as well as high-throughput genetic screens. This review summarizes recent technology developments in this area and their applications to modern biomedical challenges. We also discuss remaining limitations and necessary future directions for this field.

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Section: Site-specific Epigenome Editingmentioning

confidence: 99%

Editing the epigenome: technologies for programmable transcription and epigenetic modulation

et al. 2016

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“…In addition, Dr. Wang demonstrated that there was a non-reciprocal competition effect between partial and perfect complementary targets caused by different miRNA loss rate in these two types of regulations. In another talk, Dr. Zhen Xie (Tsinghua University, China) demonstrated a library of reversible transcription activator-like effector repressors (TALERs) that bound designed hybrid promoters and exerted transcriptional repression through steric hindrance of key transcriptional initiation elements [24]. Dr. Xie showed that the performance of modularly assembled TALER cascade and switch circuits could be quantitatively predicted by using the input-output transfer functions of individual TALER constituents, indicating that this TALER library could be a valuable toolkit to facilitate modular engineering of synthetic circuits.…”

Section: Pathways and Network In Actionmentioning

confidence: 99%

Quantitative biology: from genes, cells to networks

Xie

2015

Quant. Biol.

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Quantitative biology is an exciting emerging field that focuses on using systematic and quantitative approaches and technologies to analyze and integrate biological systems, construct and model engineered life systems, and even manipulate biological processes and functions. The advance of high-throughput biotechnologies has shifted the paradigm of biological researches from focusing on intricacies of molecular components to understanding how biological systems function in terms of modules and networks. On October 13-17 in 2014, more than 200 participants gathered at Cold Spring Harbor Asia Conference on Quantitative Biology in Suzhou, China, to exchange and discuss recent advances in quantitatively understanding of biological systems at the scale of genes, cells, and integrated networks. The conference was led by Michael Q. Zhang (University of Texas at Dallas, USA; Tsinghua University, China), Chao Tang (Peking University, China) and Terence Hwa (University of California San Diego, USA). In this report, we highlighted a few themes among 32 oral presentations and 34 poster presentations brought by this conference. PROCEEDING AND HIGHLIGHT TALKS Regulatory interactionsThe first lecture was given by Dr. Johan Elf (Uppsala University, Sweden). Dr. Elf demonstrated an assay for measuring the rate of dissociation for a LacI repressor from an individual chromosomal operator site at the level of individual molecules in E. coli. By combining with the corresponding association rate measurement [1], Dr. Elf tested the commonly used assumption that transcription factor (TF) kinetics can be considered to be at equilibrium and that the gene expression is proportional to the time the operator is free. In the second talk of this section, Dr. Gary D. Stormo (Washington University, USA) presented his recent progress in determining optimal models for transcription factor specificity by a newly developed experimental method, Spec-seq and the corresponding algorithms for data analysis [2,3]. The Spec-seq offered unprecedented accuracy for determining relative binding affinities to thousands of binding sites in parallel, which helped uncover new findings regarding the binding characteristics of Lac repressor [4]. In Dr. Hualin Shi's lecture (Institute of Theoretical Physics, Chinese Academy of Sciences, China), he quantified sequence-function relations for small RNA mediated gene silencing using the well-characterized small RNA RyhB and its target sodB in E. coli [5]. His results support the applicability of the thermodynamic model in predicting RNA-RNA interaction and suggest that both the kinetic and thermodynamic process of base-pairing between sRNA and mRNA determines the regulatory level. Dr. Xiling Shen (Cornell University, USA) discussed how miR-34a controls the asymmetric division of colon cancer stem cells by using quantitative single-cell analysis [6]. He showed that miR-34a targets Numb to form an incoherent feedforward loop (IFFL), which enhances bimodality by orders of magnitude. In addition, he demonstrated that the IF...

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“…In certain circumstances, limited durations or transmission of artificial manipulation may be preferable. Furthermore, the versatility and multiplex capacity of these genome engineering tools combined with the recent advances in synthetic eukaryotic genetic circuit designs (Khalil et al 2012;Slusarczyk et al 2012;Esvelt et al 2013;Farzadfard et al 2013;Daringer et al 2014;Kabadi et al 2014;Kiani et al 2014;Nielsen and Voigt 2014;Nissim et al 2014;O'Connell et al 2014;Li et al 2015b;Zalatan et al 2015) may lead to the next generation of cell therapies (Fig. 3B).…”

Section: Genome Engineering To Model Disease and Develop Therapeuticsmentioning

confidence: 99%

Enabling functional genomics with genome engineering

Hilton

Gersbach

2015

Genome Res.

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Advances in genome engineering technologies have made the precise control over genome sequence and regulation possible across a variety of disciplines. These tools can expand our understanding of fundamental biological processes and create new opportunities for therapeutic designs. The rapid evolution of these methods has also catalyzed a new era of genomics that includes multiple approaches to functionally characterize and manipulate the regulation of genomic information. Here, we review the recent advances of the most widely adopted genome engineering platforms and their application to functional genomics. This includes engineered zinc finger proteins, TALEs/TALENs, and the CRISPR/Cas9 system as nucleases for genome editing, transcription factors for epigenome editing, and other emerging applications. We also present current and potential future applications of these tools, as well as their current limitations and areas for future advances.

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Modular construction of mammalian gene circuits using TALE transcriptional repressors

Cited by 80 publications

References 50 publications

Editing the epigenome: technologies for programmable transcription and epigenetic modulation

Editing the epigenome: technologies for programmable transcription and epigenetic modulation

Quantitative biology: from genes, cells to networks

Enabling functional genomics with genome engineering

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