The ancient Z-DNA and Z-RNA specific Zα fold has evolved modern roles in immunity and transcription through the natural selection of flipons

Royal Society Open Science, Journal Year: 2024, Volume and Issue: 11(6)

Published: June 1, 2024

The Zα fold specifically binds to both Z-DNA and Z-RNA, left-handed nucleic acid structures that form under physiological conditions are encoded by flipons. I trace the back unicellular organisms representing all three domains of life realm giant nucleocytoplasmic DNA viruses (NCVs). canonical is present in earliest known holozoan symbiont Capsaspora owczarzaki persists vertebrates some invertebrates, but not plants or fungi. In metazoans, starting with porifera, incorporated into double-stranded RNA editing enzyme ADAR reflects an early relationship NCV. vertebrates, also ZBP1 PKZ proteins recognize host-derived Z-RNAs defend against modern-day viruses. A related fold, likely bind Z-DNA, thought modulate gene expression, including a subset prokaryote arsR p15 (PC4) family algae. Other variants probably play more general role reinitiation transcription include archaeal human factor E polymerase 3 subunit C proteins. roles immunity underlie natural selection

Language: Английский

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Systemic lupus erythematosus genetics: insights into pathogenesis and implications for therapy

Nature Reviews Rheumatology, Journal Year: 2024, Volume and Issue: 20(10), P. 635 - 648

Published: Sept. 4, 2024

Language: Английский

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Z-DNA formation in promoters conserved between human and mouse are associated with increased transcription reinitiation rates

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Aug. 1, 2024

A long-standing question concerns the role of Z-DNA in transcription. Here we use a deep learning approach DeepZ that predicts Z-flipons based on DNA sequence, structural properties nucleotides and omics data. We examined are conserved between human mouse genomes after generating whole-genome Z-flipon maps then validated them by orthogonal approaches high resolution chemical mapping transformer algorithm Z-DNABERT. For mouse, revealed similar pattern transcription factors, chromatin remodelers, histone marks associated with Z-flipons. found significant enrichment alternative bidirectional promoters neurogenesis genes. show increased experimentally determined reinitiation rates compared to without Z-flipons, but affecting elongation or pausing. Our findings support model where engage Transcription Factor E impact phenotype enabling reset preinitiation complexes when active, suppression gene expression engaged repressive complexes.

Language: Английский

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The role of DNA in the pathogenesis of SLE: DNA as a molecular chameleon

Annals of the Rheumatic Diseases, Journal Year: 2024, Volume and Issue: 83(7), P. 830 - 837

Published: May 15, 2024

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterised by antibodies to DNA (anti-DNA) and other nuclear macromolecules. Anti-DNA are markers for classification activity promote pathogenesis forming immune complexes that deposit in the tissue or stimulate cytokine production. Studies on antibody response have focused primarily conformation of known as B-DNA, classic right-handed double helix. Among conformations DNA, Z-DNA left-handed helix with zig-zag backbone; hence, term Z-DNA. formation favoured certain base sequences, energetically unfavourable flip from B-DNA dependent conditions. differs its immunogenicity animal models. Furthermore, anti-Z-DNA antibodies, but not anti-B-DNA can be present otherwise healthy individuals. In SLE, occur association cross-reactive response, rising falling together. While formed transiently chromosomal stably bacterial biofilms; biofilms provide protection against antibiotics challenges including elements host defence. The high GC content also favours do DNA-binding proteins origin. Together, these findings suggest sources enhance and, production bind both As such, act molecular chameleon that, when stabilised conformation, drive autoimmunity.

Language: Английский

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A Compendium of G-flipon Biological Functions that have Experimental Validation

Published: Aug. 23, 2024

As with all new fields of discovery, work on the biological role G-quadruplexes (GQ) has produced a number results that at first glance are quite baffling, sometimes because they do not fit well together, but mostly different from commonly held expectations. Like other classes flipons, those form have repeat sequence motif enables fold. The canonical DNA (G3N1-7)3G3, where N is any nucleotide and G guanine, feature under active selection in avian mammalian genomes. involvement G-flipons genome maintenance traces back to invertebrate C. elegans ancient repair pathways. A for GQ transcription supported by observation yeast Rap1 protein binds both B-DNA, sequence-specific manner, GQ, structure-specific through same helix. Other factors (TF) also engage conformations. RNAs can modulate formation manner cellular machinery as localized TF, linking RNA world modern world. coevolution proteins studies early embryonic development, transient potentially coordinates epigenetic specification cell fate.

Language: Английский

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Flipons enable genomes to learn by intermediating the exchange of energy for information

Journal of The Royal Society Interface, Journal Year: 2025, Volume and Issue: 22(224)

Published: March 1, 2025

Recent findings have confirmed the long-held belief that alternative DNA conformations encoded by genetic elements called flipons important biological roles. Many of these structures are formed sequences originally spread throughout human genome endogenous retroelements (ERE) captured 50% territory before being disarmed. Only 2.6% remaining codes for proteins. Other organisms instead streamlined their genomes eliminating invasive and other repeat elements. The question arises, why retain any ERE at all? A new synthesis suggests enable to learn programme context-specific readout information altering transcripts produced. exchange energy is mediated through changes in topology. Here I provide a formulation how describe underlying p-bit algorithm which tuned. framework strategies therapeutic reprogramming cells.

Language: Английский

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Triplexes Color the Chromaverse by Modulating Nucleosome Phasing and Anchoring Chromatin Condensates

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4032 - 4032

Published: April 24, 2025

Genomic sequences that form three-stranded triplexes (TPXs) under physiological conditions (called T-flipons) play an important role in defining DNA nucleosome-free regions (NFRs). Within these NFRs, other flipon types can cycle conformations to actuate gene expression. The transcripts read from the NFR condensates engage proteins and small RNAs. helicases bound then trigger RNA polymerase release by dissociating 7SK ribonucleoprotein. TPXs formed usually incorporate as third strand. made only arise mostly during replication. Many (sRNAs) long noncoding (lncRNA) direct TPX formation. with circular RNAs have greater stability specificity than those linear LncRNAs affect local expression through formation transcriptional interference. seeded lncRNAs are updated feedback loops involving genes they regulate. Some also target distant loci a sequence-specific manner. Overall, rapidly evolve adding or subtracting sequence motifs modify nucleate. show less conservation protein-coding sequences. sRNAs help place nucleosomes restrict endogenous retroelement (ERE) silencing of EREs starts early embryogenesis is essential for bootstrapping development. Once system set, different role, notable enrichment Short Interspersed Nuclear Repeats (SINEs) Enhancer–Promoter condensates. highly programmable TPX-dependent processes create chromaverse capable many complexities.

Language: Английский

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The Binding Properties of Antibodies to Z-DNA in the Sera of Normal Healthy Subjects

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2556 - 2556

Published: Feb. 22, 2024

Antibodies to DNA are a diverse set of antibodies that bind sites on DNA, polymeric macromolecule displays various conformations. In previous study, we showed sera normal healthy subjects (NHS) contain IgG Z-DNA, left-handed helix with zig-zig backbone. Recent studies have demonstrated the presence Z-DNA in bacterial biofilms, suggesting source this conformation induce responses. To characterize further used an ELISA assay brominated poly(dGdC) as and determined isotype these their binding properties. Results indicate NHS IgM IgA well anti-Z-DNA antibodies. As shown by effects ionic strength association dissociation assays, primarily electrostatic interactions; type differs from induced immunized animals which non-ionic interactions. Furthermore, urea caused at molar concentrations much lower than those for These also fecal water. Together, demonstrate occur commonly immunity may arise response origin.

Language: Английский

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A Compendium of G-Flipon Biological Functions That Have Experimental Validation

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(19), P. 10299 - 10299

Published: Sept. 25, 2024

As with all new fields of discovery, work on the biological role G-quadruplexes (GQs) has produced a number results that at first glance are quite baffling, sometimes because they do not fit well together, but mostly different from commonly held expectations. Like other classes flipons, those form have repeat sequence motif enables fold. The canonical DNA (G3N1–7)3G3, where N is any nucleotide and G guanine, feature under active selection in avian mammalian genomes. involvement G-flipons genome maintenance traces back to invertebrate Caenorhabditis elegans ancient repair pathways. GQs transcription supported by observation yeast Rap1 protein binds both B-DNA, sequence-specific manner, GQs, structure-specific through same helix. Other factors (TFs) also engage conformations actuate cellular transactions. Noncoding RNAs can modulate GQ formation manner machinery as localized TFs, linking RNA world modern world. coevolution noncoding proteins studies early embryonic development, transient coordinates epigenetic specification cell fate.

Language: Английский

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Generative Models for Prediction of Non-B DNA Structures

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 28, 2024

Abstract Motivation Deep learning methods have been successfully applied to the tasks of predicting non-B DNA structures, however model performance depends on availability experimental data for training. Experimental technologies structure detection are limited subsets that active at time an experiment and cannot detect entire functional set elements. Recently deep generative models demonstrated promising results in augmentation approach improving classifier trained augmented real generated data. Here we aimed testing diffusion comparison other explore task prediction. Results We tested denoising probabilistic implicit (DDPM DDIM), Wasserstein adversarial network (WGAN) vector quantised variational autoencoder (VQ-VAE) Z-DNA, G-quadruplexes H-DNA. showed increased quality classifiers with being best Z-DNA H-DNA while WGAN worked better G4s. Diffusion diversity all types produced novelty Since require substantial resources, distillation technique can significantly enhance sampling training models. When considering three criteria -quality samples, speed, diversity, conclude trade-off is possible between architectures such as VQ-VAE. Availability The code conducted experiments freely available https://github.com/powidla/nonB-DNA-structures-generation . Contact [email protected] Supplementary information Journal Name online.

Language: Английский

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