scholarly journals Designing Biological Circuits: Synthetic Biology Within the Operon Model and Beyond

2021 ◽  
Vol 90 (1) ◽  
Author(s):  
Max A. English ◽  
Raphaël V. Gayet ◽  
James J. Collins
Keyword(s):  
Synthetic Biology ◽  
Gene Networks ◽  
Rna Binding ◽  
Phenotypic Diversity ◽  
Annual Review ◽  
Publication Date ◽  
Modular Assembly ◽  
Dna And Rna ◽  
Regulatory Circuits ◽  
Biological Circuits

In 1961, Jacob and Monod proposed the operon model of gene regulation. At the model's core was the modular assembly of regulators, operators, and structural genes. To illustrate the composability of these elements, Jacob and Monod linked phenotypic diversity to the architectures of regulatory circuits. In this review, we examine how the circuit blueprints imagined by Jacob and Monod laid the foundation for the first synthetic gene networks that launched the field of synthetic biology in 2000. We discuss the influences of the operon model and its broader theoretical framework on the first generation of synthetic biological circuits, which were predominantly transcriptional and posttranscriptional circuits. We also describe how recent advances in molecular biology beyond the operon model—namely, programmable DNA- and RNA-binding molecules as well as models of epigenetic and posttranslational regulation—are expanding the synthetic biology toolkit and enabling the design of more complex biological circuits. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Biomolecular Systems Engineering: Unlocking the Potential of Engineered Allostery via the Lactose Repressor Topology

2021 ◽  
Vol 50 (1) ◽  
Author(s):  
Thomas M. Groseclose ◽  
Ronald E. Rondon ◽  
Ashley N. Hersey ◽  
Prasaad T. Milner ◽  
Dowan Kim ◽  
...  
Keyword(s):  
Synthetic Biology ◽  
Systems Engineering ◽  
Gene Networks ◽  
Chemical Engineering ◽  
Publication Date ◽  
Biomolecular Systems ◽  
Lactose Repressor ◽  
Unit Operations ◽  
Allosteric Communication ◽  
Logical Operations

Allosteric function is a critical component of many of the parts used to construct gene networks throughout synthetic biology. In this review, we discuss an emerging field of research and education, biomolecular systems engineering, that expands on the synthetic biology edifice—integrating workflows and strategies from protein engineering, chemical engineering, electrical engineering, and computer science principles. We focus on the role of engineered allosteric communication as it relates to transcriptional gene regulators—i.e., transcription factors and corresponding unit operations. In this review, we ( a) explore allosteric communication in the lactose repressor LacI topology, ( b) demonstrate how to leverage this understanding of allostery in the LacI system to engineer non-natural BUFFER and NOT logical operations, ( c) illustrate how engineering workflows can be used to confer alternate allosteric functions in disparate systems that share the LacI topology, and ( d) demonstrate how fundamental unit operations can be directed to form combinational logical operations. Expected final online publication date for the Annual Review of Biophysics, Volume 50 is May 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Cullin-RING Ubiquitin Ligase Regulatory Circuits: a Quarter Century Beyond the F-box Hypothesis

2021 ◽  
Vol 90 (1) ◽  
Author(s):  
J. Wade Harper ◽  
Brenda A. Schulman
Keyword(s):  
Ubiquitin Ligase ◽  
Annual Review ◽  
Publication Date ◽  
Specific Substrate ◽  
Biological Processes ◽  
Quarter Century ◽  
Cellular Decision Making ◽  
Regulatory Circuits ◽  
Ring E3

Cullin-RING ubiquitin ligases (CRLs) are dynamic modular platforms that regulate myriad biological processes through target-specific ubiquitylation. Our knowledge of this system emerged from the F-box hypothesis, posited a quarter century ago: Numerous interchangeable F-box proteins confer specific substrate recognition for a core CUL1-based RING E3 ubiquitin ligase. This paradigm has been expanded through the evolution of a superfamily of analogous modular CRLs, with five major families and over 200 different substrate-binding receptors in humans. Regulation is achieved by numerous factors organized in circuits that dynamically control CRL activation and substrate ubiquitylation. CRLs also serve as a vast landscape for developing small molecules that reshape interactions and promote targeted ubiquitylation-dependent turnover of proteins of interest. Here, we review molecular principles underlying CRL function, the role of allosteric and conformational mechanisms in controlling substrate timing and ubiquitylation, and how the dynamics of substrate receptor interchange drives the turnover of selected target proteins to promote cellular decision making. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Heart Development and Congenital Structural Heart Defects

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Lucile Houyel ◽  
Sigolène M. Meilhac
Keyword(s):  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Human Genetics ◽  
Current Knowledge ◽  
Phenotypic Diversity ◽  
Heart Defects ◽  
Annual Review ◽  
Publication Date ◽  
Research Perspectives

Congenital heart disease is the most frequent birth defect and the leading cause of death for the fetus and in the first year of life. The wide phenotypic diversity of congenital heart defects requires expert diagnosis and sophisticated repair surgery. Although these defects have been described since the seventeenth century, it was only in 2005 that a consensus international nomenclature was adopted, followed by an international classification in 2017 to help provide better management of patients. Advances in genetic engineering, imaging, and omics analyses have uncovered mechanisms of heart formation and malformation in animal models, but approximately 80% of congenital heart defects have an unknown genetic origin. Here, we summarize current knowledge of congenital structural heart defects, intertwining clinical and fundamental research perspectives, with the aim to foster interdisciplinary collaborations at the cutting edge of each field. We also discuss remaining challenges in better understanding congenital heart defects and providing benefits to patients. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Control of RNA Stability in Immunity

2021 ◽  
Vol 39 (1) ◽  
Author(s):  
Shizuo Akira ◽  
Kazuhiko Maeda
Keyword(s):  
Immune Responses ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Rna Stability ◽  
Regulatory Elements ◽  
Annual Review ◽  
Publication Date ◽  
Posttranscriptional Control ◽  
Microrna Regulation ◽  
Functional Roles

Posttranscriptional control of mRNA regulates various biological processes, including inflammatory and immune responses. RNA-binding proteins (RBPs) bind cis-regulatory elements in the 3′ untranslated regions (UTRs) of mRNA and regulate mRNA turnover and translation. In particular, eight RBPs (TTP, AUF1, KSRP, TIA-1/TIAR, Roquin, Regnase, HuR, and Arid5a) have been extensively studied and are key posttranscriptional regulators of inflammation and immune responses. These RBPs sometimes collaboratively or competitively bind the same target mRNA to enhance or dampen regulatory activities. These RBPs can also bind their own 3′ UTRs to negatively or positively regulate their expression. Both upstream signaling pathways and microRNA regulation shape the interactions between RBPs and target RNA. Dysregulation of RBPs results in chronic inflammation and autoimmunity. Here, we summarize the functional roles of these eight RBPs in immunity and their associated diseases. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Perfecting Targeting in CRISPR

2021 ◽  
Vol 55 (1) ◽  
Author(s):  
Hainan Zhang ◽  
Tong Li ◽  
Yidi Sun ◽  
Hui Yang
Keyword(s):  
Rna Editing ◽  
Online Publication ◽  
Genome Engineering ◽  
Basic Research ◽  
Annual Review ◽  
Publication Date ◽  
Full Potential ◽  
Dna And Rna ◽  
Genome Wide ◽  
Target Effects

CRISPR-based genome editing holds promise for genome engineering and other applications in diverse organisms. Defining and improving the genome-wide and transcriptome-wide specificities of these editing tools are essential for realizing their full potential in basic research and biomedical therapeutics. This review provides an overview of CRISPR-based DNA- and RNA-editing technologies, methods to quantify their specificities, and key solutions to reduce off-target effects for research and improve therapeutic applications. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Adenosine Deaminases Acting on RNA (ADARs) and Viral Infections

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Christian K. Pfaller ◽  
Cyril X. George ◽  
Charles E. Samuel
Keyword(s):  
Messenger Rna ◽  
Measles Virus ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Annual Review ◽  
Publication Date ◽  
Alternative Promoters ◽  
Hepatitis D ◽  
Alu Elements ◽  
Adenosine Deaminases

C6 deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA) is catalyzed by a family of enzymes known as ADARs (adenosine deaminases acting on RNA) encoded by three genes in mammals. Alternative promoters and splicing produce two ADAR1 proteins, an interferon-inducible cytoplasmic p150 and a constitutively expressed p110 that like ADAR2 is a nuclear enzyme. ADAR3 lacks deaminase activity. A-to-I editing occurs with both viral and cellular RNAs. Deamination activity is dependent on dsRNA substrate structure and regulatory RNA-binding proteins and ranges from highly site selective with hepatitis D RNA and glutamate receptor precursor messenger RNA (pre-mRNA) to hyperediting of measles virus and polyomavirus transcripts and cellular inverted Alu elements. Because I base-pairs as guanosine instead of A, editing can alter mRNA decoding, pre-mRNA splicing, and microRNA silencing. Editing also alters dsRNA structure, thereby suppressing innate immune responses including interferon production and action. Expected final online publication date for the Annual Review of Virology, Volume 8 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Transcriptional Pausing as a Mediator of Bacterial Gene Regulation

2021 ◽  
Vol 75 (1) ◽  
Author(s):  
Robert Landick
Keyword(s):  
Rna Polymerase ◽  
Molecular Mechanisms ◽  
Annual Review ◽  
Publication Date ◽  
Rna Sequences ◽  
Bacterial Gene ◽  
Dna And Rna ◽  
A Genome ◽  
Transcript Elongation ◽  
Transcriptional Pausing

Cellular life depends on transcription of DNA by RNA polymerase to express genetic information. RNA polymerase has evolved not just to read information from DNA and write it to RNA but also to sense and process information from the cellular and extracellular environments. Much of this information processing occurs during transcript elongation, when transcriptional pausing enables regulatory decisions. Transcriptional pauses halt RNA polymerase in response to DNA and RNA sequences and structures at locations and times that help coordinate interactions with small molecules and transcription factors important for regulation. Four classes of transcriptional pause signals are now evident after decades of study: elemental pauses, backtrack pauses, hairpin-stabilized pauses, and regulator-stabilized pauses. In this review, I describe current understanding of the molecular mechanisms of these four classes of pause signals, remaining questions about how RNA polymerase responds to pause signals, and the many exciting directions now open to understand pausing and the regulation of transcript elongation on a genome-wide scale. Expected final online publication date for the Annual Review of Microbiology, Volume 75 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Single cell RNA-seq reveals genes vital to in vitro fertilized embryos and parthenotes in pigs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zhi-Qiang Du ◽  
Hao Liang ◽  
Xiao-Man Liu ◽  
Yun-Hua Liu ◽  
Chonglong Wang ◽  
...  
Keyword(s):  
Embryo Development ◽  
Gene Networks ◽  
Regulatory Networks ◽  
Rna Binding ◽  
Expression Patterns ◽  
Early Embryo ◽  
Specific Factor ◽  
Early Embryos ◽  
Genome Activation

AbstractSuccessful early embryo development requires the correct reprogramming and configuration of gene networks by the timely and faithful execution of zygotic genome activation (ZGA). However, the regulatory principle of molecular elements and circuits fundamental to embryo development remains largely obscure. Here, we profiled the transcriptomes of single zygotes and blastomeres, obtained from in vitro fertilized (IVF) or parthenogenetically activated (PA) porcine early embryos (1- to 8-cell), focusing on the gene expression dynamics and regulatory networks associated with maternal-to-zygote transition (MZT) (mainly maternal RNA clearance and ZGA). We found that minor and major ZGAs occur at 1-cell and 4-cell stages for both IVF and PA embryos, respectively. Maternal RNAs gradually decay from 1- to 8-cell embryos. Top abundantly expressed genes (CDV3, PCNA, CDR1, YWHAE, DNMT1, IGF2BP3, ARMC1, BTG4, UHRF2 and gametocyte-specific factor 1-like) in both IVF and PA early embryos identified are of vital roles for embryo development. Differentially expressed genes within IVF groups are different from that within PA groups, indicating bi-parental and maternal-only embryos have specific sets of mRNAs distinctly decayed and activated. Pathways enriched from DEGs showed that RNA associated pathways (RNA binding, processing, transport and degradation) could be important. Moreover, mitochondrial RNAs are found to be actively transcribed, showing dynamic expression patterns, and for DNA/H3K4 methylation and transcription factors as well. Taken together, our findings provide an important resource to investigate further the epigenetic and genome regulation of MZT events in early embryos of pigs.

scholarly journals Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yogeeshwar Ajjugal ◽  
Narendar Kolimi ◽  
Thenmalarchelvi Rathinavelan
Keyword(s):  
Rna Binding ◽  
Trinucleotide Repeat ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Repeat Expansion ◽  
Mobility Shift ◽  
Cgg Repeat ◽  
Dna And Rna ◽  
Structural Choice ◽  
Sense Strand

AbstractCGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C canonical base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.

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