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Current Opinion in Structural Biology Aug 2022The structural unit of eukaryotic chromatin is a nucleosome, comprising two histone H2A/H2B heterodimers and one histone (H3/H4) tetramer, wrapped around by ∼146-bp... (Review)
Review
The structural unit of eukaryotic chromatin is a nucleosome, comprising two histone H2A/H2B heterodimers and one histone (H3/H4) tetramer, wrapped around by ∼146-bp core DNA and linker DNA. Flexible histone tails sticking out from the core undergo posttranslational modifications that are responsible for various epigenetic functions. Recently, the functional dynamics of histone tails and their modulation within the nucleosome and nucleosomal complexes have been investigated by integrating NMR, molecular dynamics simulations, and cryo-electron microscopy approaches. In particular, recent NMR studies have revealed correlations in the structures of histone N-terminal tails between H2A and H2B, as well as between H3 and H4 depending on linker DNA, suggesting that histone tail networks exist even within the nucleosome.
Topics: Chromatin; Cryoelectron Microscopy; DNA; Histones; Nucleosomes
PubMed: 35863166
DOI: 10.1016/j.sbi.2022.102436 -
Chemistry (Weinheim An Der Bergstrasse,... Apr 2023Eukaryotic transcription factors (TFs) are the final integrators of a complex molecular feedback mechanism that interfaces with the genome, consolidating information for... (Review)
Review
Eukaryotic transcription factors (TFs) are the final integrators of a complex molecular feedback mechanism that interfaces with the genome, consolidating information for transcriptional regulation. TFs consist of both structured DNA-binding domains and long intrinsically disordered regions (IDRs) embedded with motifs linked to transcriptional control. It is now well established that the dynamic multifunctionality of IDRs is the basis for a wide spectrum of TF functions necessary to navigate and regulate the human genome. This review dissects the chemical features of TF IDRs that endow them with structural plasticity that is central to their functions in the nucleus. Sequence analysis of a set of over 1600 human TFs through AlphaFold was used to identify key features of their IDRs. Recent studies were then highlighted to illustrate IDR involvement in processes such as protein interactions, DNA binding and specificity, chromatin opening, and phase separation. To expand our understanding of TF functions, future directions are suggested for integrating experiments and simulations, from in vitro to living systems.
Topics: Humans; Transcription Factors; Intrinsically Disordered Proteins; Eukaryota; DNA
PubMed: 36648282
DOI: 10.1002/chem.202203369 -
Biochemical Society Transactions Aug 2020Synthetic gene circuits allow programming in DNA the expression of a phenotype at a given environmental condition. The recent integration of memory systems with gene... (Review)
Review
Synthetic gene circuits allow programming in DNA the expression of a phenotype at a given environmental condition. The recent integration of memory systems with gene circuits opens the door to their adaptation to new conditions and their re-programming. This lays the foundation to emulate neuromorphic behaviour and solve complex problems similarly to artificial neural networks. Cellular products such as DNA or proteins can be used to store memory in both digital and analog formats, allowing cells to be turned into living computing devices able to record information regarding their previous states. In particular, synthetic gene circuits with memory can be engineered into living systems to allow their adaptation through reinforcement learning. The development of gene circuits able to adapt through reinforcement learning moves Sciences towards the ambitious goal: the bottom-up creation of a fully fledged living artificial intelligence.
Topics: Artificial Intelligence; DNA; Gene Regulatory Networks; Genes, Synthetic
PubMed: 32756895
DOI: 10.1042/BST20200008 -
Biosensors & Bioelectronics Nov 2016Over the last few decades, an increased demand has emerged for integrating biosensors with microfluidic- and nanofluidic-based lab-on-chip (LOC) devices for... (Review)
Review
Over the last few decades, an increased demand has emerged for integrating biosensors with microfluidic- and nanofluidic-based lab-on-chip (LOC) devices for point-of-care (POC) diagnostics, in the medical industry and environmental monitoring of pathogenic threat agents. Such a merger of microfluidics with biosensing technologies allows for the precise control of volumes, as low as one nanolitre and the integration of various types of bioassays on a single miniaturized platform. This integration offers several favorable advantages, such as low reagent consumption, automation of sample preparation, reduction in processing time, low cost analysis, minimal handling of hazardous materials, high detection accuracy, portability and disposability. This review provides a synopsis of the most recent developments in the microfluidic-integrated biosensing field by delineating the fundamental theory of microfluidics, fabrication techniques and a detailed account of the various transduction methods that are employed. Lastly, the review discusses state-of-the-art DNA biosensors with a focus on optical DNA biosensors.
Topics: Animals; Biosensing Techniques; DNA; Equipment Design; Humans; Lab-On-A-Chip Devices; Microfluidic Analytical Techniques; Point-of-Care Systems; Transducers
PubMed: 27179566
DOI: 10.1016/j.bios.2016.05.009 -
Nature Oct 2023The past decades have witnessed the evolution of electronic and photonic integrated circuits, from application specific to programmable. Although liquid-phase DNA...
The past decades have witnessed the evolution of electronic and photonic integrated circuits, from application specific to programmable. Although liquid-phase DNA circuitry holds the potential for massive parallelism in the encoding and execution of algorithms, the development of general-purpose DNA integrated circuits (DICs) has yet to be explored. Here we demonstrate a DIC system by integration of multilayer DNA-based programmable gate arrays (DPGAs). We find that the use of generic single-stranded oligonucleotides as a uniform transmission signal can reliably integrate large-scale DICs with minimal leakage and high fidelity for general-purpose computing. Reconfiguration of a single DPGA with 24 addressable dual-rail gates can be programmed with wiring instructions to implement over 100 billion distinct circuits. Furthermore, to control the intrinsically random collision of molecules, we designed DNA origami registers to provide the directionality for asynchronous execution of cascaded DPGAs. We exemplify this by a quadratic equation-solving DIC assembled with three layers of cascade DPGAs comprising 30 logic gates with around 500 DNA strands. We further show that integration of a DPGA with an analog-to-digital converter can classify disease-related microRNAs. The ability to integrate large-scale DPGA networks without apparent signal attenuation marks a key step towards general-purpose DNA computing.
Topics: Algorithms; DNA; Oligonucleotides; Computers, Molecular; MicroRNAs; Disease
PubMed: 37704731
DOI: 10.1038/s41586-023-06484-9 -
Bioconjugate Chemistry Jan 2023Over the past 40 years, structural and dynamic DNA nanotechnologies have undoubtedly demonstrated to be effective means for organizing matter at the nanoscale and... (Review)
Review
Over the past 40 years, structural and dynamic DNA nanotechnologies have undoubtedly demonstrated to be effective means for organizing matter at the nanoscale and reconfiguring equilibrium structures, in a predictable fashion and with an accuracy of a few nanometers. Recently, novel concepts and methodologies have been developed to integrate nonequilibrium dynamics into DNA nanostructures, opening the way to the construction of synthetic materials that can adapt to environmental changes and thus acquire new properties. In this Review, we summarize the strategies currently applied for the construction of synthetic DNA filaments and conclude by reporting some recent and most relevant examples of DNA filaments that can emulate typical structural and dynamic features of the cytoskeleton, such as compartmentalization in cell-like vesicles, support for active transport of cargos, sustained or transient growth, and responsiveness to external stimuli.
Topics: Cytoskeleton; Nanotechnology; Nanostructures; Microtubules; DNA
PubMed: 36174970
DOI: 10.1021/acs.bioconjchem.2c00312 -
Microbiology Spectrum Apr 2015Sleeping Beauty (SB) is a synthetic transposon that was constructed based on sequences of transpositionally inactive elements isolated from fish genomes. SB is a... (Review)
Review
Sleeping Beauty (SB) is a synthetic transposon that was constructed based on sequences of transpositionally inactive elements isolated from fish genomes. SB is a Tc1/mariner superfamily transposon following a cut-and-paste transpositional reaction, during which the element-encoded transposase interacts with its binding sites in the terminal inverted repeats of the transposon, promotes the assembly of a synaptic complex, catalyzes excision of the element out of its donor site, and integrates the excised transposon into a new location in target DNA. SB transposition is dependent on cellular host factors. Transcriptional control of transposase expression is regulated by the HMG2L1 transcription factor. Synaptic complex assembly is promoted by the HMGB1 protein and regulated by chromatin structure. SB transposition is highly dependent on the nonhomologous end joining (NHEJ) pathway of double-strand DNA break repair that generates a transposon footprint at the excision site. Through its association with the Miz-1 transcription factor, the SB transposase downregulates cyclin D1 expression that results in a slowdown of the cell-cycle in the G1 phase, where NHEJ is preferentially active. Transposon integration occurs at TA dinucleotides in the target DNA, which are duplicated at the flanks of the integrated transposon. SB shows a random genome-wide insertion profile in mammalian cells when launched from episomal vectors and "local hopping" when launched from chromosomal donor sites. Some of the excised transposons undergo a self-destructive autointegration reaction, which can partially explain why longer elements transpose less efficiently. SB became an important molecular tool for transgenesis, insertional mutagenesis, and gene therapy.
Topics: Animals; DNA; DNA Transposable Elements; Fishes; Recombination, Genetic; Transposases
PubMed: 26104705
DOI: 10.1128/microbiolspec.MDNA3-0042-2014 -
Advances in Experimental Medicine and... 2018Upon infection and depending on the infected cell type, human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) can replicate or enter a state of latency. HHV-6A and HHV-6B can... (Review)
Review
Upon infection and depending on the infected cell type, human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) can replicate or enter a state of latency. HHV-6A and HHV-6B can integrate their genomes into host chromosomes as one way to establish latency. Viral integration takes place near the subtelomeric/telomeric junction of chromosomes. When HHV-6 infection and integration occur in gametes, the virus can be genetically transmitted. Inherited chromosomally integrated HHV-6 (iciHHV-6)-positive individuals carry one integrated HHV-6 copy per somatic cell. The prevalence of iciHHV-6 individuals varies between 0.6% and 2%, depending on the geographical region sampled. In this chapter, the mechanisms leading to viral integration and reactivation from latency, as well as some of the biological and medical consequences associated with iciHHV-6, were discussed.
Topics: Animals; Chromosomes, Human; DNA, Viral; Herpesvirus 6, Human; Humans; Roseolovirus Infections; Telomere; Virus Integration
PubMed: 29896669
DOI: 10.1007/978-981-10-7230-7_10 -
Topics in Current Chemistry (Cham) Apr 2020Cellular functions rely on a series of organized and regulated multienzyme cascade reactions. The catalytic efficiencies of these cascades depend on the precise spatial... (Review)
Review
Cellular functions rely on a series of organized and regulated multienzyme cascade reactions. The catalytic efficiencies of these cascades depend on the precise spatial organization of the constituent enzymes, which is optimized to facilitate substrate transport and regulate activities. Mimicry of this organization in a non-living, artificial system would be very useful in a broad range of applications-with impacts on both the scientific community and society at large. Self-assembled DNA nanostructures are promising applications to organize biomolecular components into prescribed, multidimensional patterns. In this review, we focus on recent progress in the field of DNA-scaffolded assembly and confinement of multienzyme reactions. DNA self-assembly is exploited to build spatially organized multienzyme cascades with control over their relative distance, substrate diffusion paths, compartmentalization and activity actuation. The combination of addressable DNA assembly and multienzyme cascades can deliver breakthroughs toward the engineering of novel synthetic and biomimetic reactors.
Topics: DNA; Enzymes; Protein Engineering
PubMed: 32248317
DOI: 10.1007/s41061-020-0299-3 -
Physical Chemistry Chemical Physics :... Jun 2023DNA's charge transfer and self-assembly characteristics have made it a hallmark of molecular electronics for the past two decades. A fast and efficient charge transfer...
DNA's charge transfer and self-assembly characteristics have made it a hallmark of molecular electronics for the past two decades. A fast and efficient charge transfer mechanism with programmable properties using DNA nanostructures is required for DNA-based nanoelectronic applications and devices. The ability to integrate DNA with inorganic substrates becomes critical in this process. Such integrations may affect the conformation of DNA, altering its charge transport properties. Thus, using molecular dynamics simulations and first-principles calculations in conjunction with Green's function approach, we explore the impact of the Au (111) substrate on the conformation of DNA and analyze its effect on the charge transport. Our results indicate that DNA sequence, leading to its molecular conformation on the Au substrate, is critical to engineer charge transport properties. We demonstrate that DNA fluctuates on a gold substrate, sampling various distinct conformations over time. The energy levels, spatial locations of molecular orbitals and the DNA/Au contact atoms can differ between these distinct conformations. Depending on the sequence, at the HOMO, the charge transmission differs up to 60 times between the top ten conformations. We demonstrate that the relative positions of the nucleobases are critical in determining the conformations and the coupling between orbitals. We anticipate that these results can be extended to other inorganic surfaces and pave the way for understanding DNA-inorganic interface interactions for future DNA-based electronic device applications.
Topics: Nanostructures; Gold; Molecular Conformation; DNA; Electronics
PubMed: 37309195
DOI: 10.1039/d2cp05009a