@misc{20780, abstract = {Sex-chromosome systems are highly variable across animals, but how they transition from one to another is not well understood. Diptera have undergone multiple sex-chromosome turnovers and expansions while maintaining their general chromosomal content, which makes them an ideal clade to study such transitions. We analysed more than 100 dipteran whole-genome assemblies and identified 4 new lineages that underwent sex-chromosome turnover (in addition to the 5 previously reported). We find the majority of turnovers happened in the group Schizophora, which tend to have fewer genes on the F element (the chromosome homologous to the ancestral insect X chromosome) than lower dipterans, a factor previously hypothesized to facilitate turnover. Most derived X chromosomes have higher GC content than autosomes, consistent with a high prevalence of male-achiasmy in Diptera. In addition, an excess of gene movement out of the X is detected for most of these new X chromosomes, and many of these moved genes have high testis expression in Drosophila, suggesting that out-of-X gene movement contributes to the long-term demasculinization of X chromosomes.}, author = {Layana Franco, Lorena Alexandra and Toups, Melissa A and Vicoso, Beatriz}, keywords = {Schizophora, sex chromosomes, sex-chromosome turnover, Diptera, genomic features, out-of-X movement.}, publisher = {Institute of Science and Technology Austria}, title = {{Causes and consequences of sex-chromosome turnovers in Diptera}}, doi = {10.15479/AT-ISTA-20780}, year = {2025}, } @article{20796, abstract = {Rapid prophase chromosome movements ensure faithful alignment of the parental homologous chromosomes and successful synapsis formation during meiosis. These movements are driven by cytoplasmic forces transmitted to the nuclear periphery, where chromosome ends are attached through transmembrane proteins. During many developmental stages a specific genome architecture with chromatin nuclear periphery contacts mediates specific gene expression. Whether chromatin is removed from the nuclear periphery as a consequence of chromosome motions or by a specific mechanism is not fully understood. Here, we identify a mechanism to remove chromatin from the nuclear periphery through vaccinia related kinase (VRK-1)–dependent phosphorylation of Barrier to Autointegration Factor 1 (BAF-1) in Caenorhabditis elegans early prophase of meiosis. Interfering with chromatin removal delays chromosome pairing, impairs synapsis, produces oocytes with abnormal chromosomes and elevated apoptosis. Long read sequencing reveals deletions and duplications in offspring lacking VRK-1 underscoring the importance of the BAF-1–VRK-1 module in preserving genome stability in gametes during rapid chromosome movements.}, author = {Paouneskou, Dimitra and Baudrimont, Antoine and Kelemen, Réka K and Elkrewi, Marwan N and Graf, Angela and Moukbel Ali Aldawla, Shehab and Kölbl, Claudia and Tiemann-Boege, Irene and Vicoso, Beatriz and Jantsch, Verena}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{BAF-1–VRK-1 mediated release of meiotic chromosomes from the nuclear periphery is important for genome integrity}}, doi = {10.1038/s41467-025-65420-9}, volume = {16}, year = {2025}, } @article{20797, abstract = {Quantum key distribution (QKD) offers a theoretically secure method to share secret keys, yet practical implementations face challenges due to noise and loss over long-distance channels. Traditional QKD protocols require extensive noise compensation, hindering their industrial scalability and lowering the achievable key rates. Alternative protocols encode logical qubits in noise-resilient states but at the cost of using many physical qubits, increasing susceptibility to loss and limiting transmission distance. In this work, we introduce a logical-qubit encoding that uses antisymmetric Bell states in the continuous photonic degrees of freedom, frequency and time. By leveraging the continuous space, we overcome this noise-loss robustness trade-off by minimizing the number of photons per logical qubit while optimizing the encoding resilience over noise fluctuations. We analyze the security of our encoding and demonstrate its robustness compared to existing state-of-the-art protocols. This approach provides a path toward scalable, efficient QKD implementations under realistic noise conditions.}, author = {Seabrook, Hannah and Lavie, Emilien and Strömberg, Karl T and Stafford, Matthew P. and Rubino, Giulia}, issn = {2331-7019}, journal = {Physical Review Applied}, number = {2}, publisher = {American Physical Society}, title = {{Surpassing the loss-noise robustness trade-off in quantum key distribution}}, doi = {10.1103/xq2l-r4r7}, volume = {24}, year = {2025}, } @unpublished{20804, abstract = {RNA polymerase II (Pol II) must be assembled in the cytoplasm before it enters the nucleus, where it transcribes protein-coding genes. Although transcription by Pol II is intensively studied, how this central multi-subunit enzyme is made and the role of dedicated factors remains unclear. Here, we report the integrative structural analysis of a native human Pol II from the cytoplasm captured near the end of biogenesis. The complex contained Gdown1 and three biogenesis factors – RPAP2 and the critical small GTPases GPN1 and GPN3. Cryo-EM analysis of the complex revealed how Gdown1 and RPAP2 associate with Pol II and prevent the premature association of transcription factors. Further biochemical and cryo-EM analysis revealed how RPAP2 recruits GPN1–GPN3 to the complex, and how the assembly of the RPAP2–GPN1–GPN3 complex is controlled by GTP hydrolysis. The combined results uncover a network of interactions that chaperone cytoplasmic Pol II to prevent aberrant interactions, reveal a GTP-controlled switch during the final stages of Pol II biogenesis, and suggest a general mechanism for the action of GPN-loop GTPase family of enzymes.}, author = {Hlavata, Annamaria and Neuditschko, Benjamin and Schellhaas, Ulla and Plaschka, Clemens and Herzog, Franz and Bernecky, Carrie A}, publisher = {bioRxiv}, title = {{Structure of cytoplasmic RNA polymerase II}}, doi = {10.64898/2025.12.10.692585}, year = {2025}, } @article{20814, abstract = {We characterize all semigroups sandwiched between the semigroup of a Dirichlet form and the semigroup of its active main part. In case the Dirichlet form is regular, we give a more explicit description of the quadratic forms of the sandwiched semigroups in terms of pairs consisting of an open set and a measure on an abstract boundary.}, author = {Keller, Matthias and Lenz, Daniel and Schmidt, Marcel and Schwarz, Michael and Wirth, Melchior}, issn = {1572-929X}, journal = {Potential Analysis}, publisher = {Springer Nature}, title = {{Boundary representations of intermediate forms between a regular Dirichlet form and its active main part}}, doi = {10.1007/s11118-025-10251-y}, volume = {64}, year = {2025}, } @article{20816, abstract = {Background: DNA methylation (DNAm) can regulate gene expression, and its genome-wide patterns (epigenetic scores or EpiScores) can act as biomarkers for complex traits. The relative stability of methylation profiles may enable better assessment of chronic exposures compared to single time-point protein measures. We present the first large-scale epigenetic study of the highly-abundant serum proteome measured via ultra-high throughput mass spectrometry in 14,671 samples from the Generation Scotland cohort. We further demonstrate the first large-scale comparison of protein EpiScores and their respective proteins as predictors of incident cardiovascular disease. Results: Marginal epigenome-wide association models, adjusting for age, sex, measurement batch, estimated white cell proportions, BMI, smoking and methylation principal components, reveal 15,855 significant CpG – protein associations across 125 of 133 proteins PBonferroni < 2.71 × 10-10. Bayesian epigenome-wide association studies of the same 133 proteins reveal 697 CpG-Protein associations (posterior inclusion probability > 0.95). 112 protein EpiScores correlate significantly with their respective protein in a holdout test-set. Of these, sixteen associate significantly with incident all-cause cardiovascular disease (Nevents=191) compared to one measured protein. Conclusions: We highlight a complex interplay between the blood-based methylome and proteome. Importantly, we show that protein EpiScores correlate with measured proteins and demonstrate that the, as-yet understudied, high-abundance proteome may yield clinically relevant biomarkers. The protein EpiScores demonstrate more significant associations with cardiovascular disease than directly measured proteins, suggesting their potential as clinical biomarkers for monitoring or predicting disease risk. We suggest that biomarker development could be enhanced by the consideration of protein EpiScores alongside measured proteins.}, author = {Robertson, Josephine A. and Bajzik, Jakub and Vernardis, Spyros and Chybowska, Aleksandra D. and Mccartney, Daniel L. and Grauslys, Arturas and Mur, Jure and Smith, Hannah M. and Campbell, Archie and Drake, Camilla and Grant, Hannah and Pearce, Jamie and Russ, Tom C. and Adkin, Poppy and White, Matthew and Brigden, Charles and Messner, Christoph B. and Porteous, David J. and Hayward, Caroline and Cox, Simon R. and Zelezniak, Aleksej and Ralser, Markus and Robinson, Matthew Richard and Marioni, Riccardo E.}, issn = {1474-760X}, journal = {Genome Biology}, publisher = {Springer Nature}, title = {{Methylome-wide association studies and epigenetic biomarker development for 133 mass spectrometry-assessed circulating proteins in 14,671 Generation Scotland participants}}, doi = {10.1186/s13059-025-03892-0}, volume = {26}, year = {2025}, } @inproceedings{20817, abstract = {We present Mechanistic PDE Networks -- a model for discovery of governing partial differential equations from data. Mechanistic PDE Networks represent spatiotemporal data as space-time dependent linear partial differential equations in neural network hidden representations. The represented PDEs are then solved and decoded for specific tasks. The learned PDE representations naturally express the spatiotemporal dynamics in data in neural network hidden space, enabling increased modeling power. Solving the PDE representations in a compute and memory-efficient way, however, is a significant challenge. We develop a native, GPU-capable, parallel, sparse and differentiable multigrid solver specialized for linear partial differential equations that acts as a module in Mechanistic PDE Networks. Leveraging the PDE solver we propose a discovery architecture that can discovers nonlinear PDEs in complex settings, while being robust to noise. We validate PDE discovery on a number of PDEs including reaction-diffusion and Navier-Stokes equations.}, author = {Pervez, Adeel A and Gavves, Efstratios and Locatello, Francesco}, booktitle = {42nd International Conference on Machine Learning}, issn = {2640-3498}, location = {Vancouver, Canada}, pages = {48962--48973}, publisher = {ML Research Press}, title = {{Mechanistic PDE networks for discovery of governing equations}}, volume = {267}, year = {2025}, } @article{20818, abstract = {This study demonstrates that Marchantia non-canonical PINs are predominantly localized to the plasma membrane, with MpPINX and MpPINW exhibiting asymmetric distribution. A newly identified miniW domain within the MpPINW hydrophilic loop governs subcellular trafficking and asymmetric PM localization of non-canonical PINs in Marchantia.}, author = {Tang, Han and Smoljan, Adrijana and Zou, Minxia and Zhang, Yuzhou and Lu, Kuan Ju and Friml, Jiří}, issn = {1365-3040}, journal = {Plant Cell and Environment}, publisher = {Wiley}, title = {{The miniW domain directs polarized membrane localization of non-canonical PINs in Marchantia polymorpha}}, doi = {10.1111/pce.70295}, year = {2025}, } @article{18753, abstract = {We continue a line of research which studies which hereditary families of digraphs have bounded dichromatic number. For a class of digraphs C, a hero in C is any digraph H such that H -free digraphs in C have bounded dichromatic number. We show that if F is an oriented star of degree at least five, the only heroes for the class of F -free digraphs are transitive tournaments. For oriented stars F of degree exactly four, we show the only heroes in F -free digraphs are transitive tournaments, or possibly special joins of transitive tournaments. Aboulker et al. characterized the set of heroes of {H,K1+P2→} -free digraphs almost completely, and we show the same characterization for the class of {H,rK1+P3→} -free digraphs. Lastly, we show that if we forbid two "valid" orientations of brooms, then every transitive tournament is a hero for this class of digraphs.}, author = {Carbonero, Alvaro and Koerts, Hidde and Moore, Benjamin and Spirkl, Sophie}, issn = {0195-6698}, journal = {European Journal of Combinatorics}, publisher = {Elsevier}, title = {{On heroes in digraphs with forbidden induced forests}}, doi = {10.1016/j.ejc.2024.104104}, volume = {125}, year = {2025}, } @article{18754, abstract = {Exploring the molecular correlates of metabolic health measures may identify their shared and unique biological processes and pathways. Molecular proxies of these traits may also provide a more objective approach to their measurement. Here, DNA methylation (DNAm) data were used in epigenome-wide association studies (EWASs) and for training epigenetic scores (EpiScores) of six metabolic traits: body mass index (BMI), body fat percentage, waist-hip ratio, and blood-based measures of glucose, high-density lipoprotein cholesterol, and total cholesterol in >17,000 volunteers from the Generation Scotland (GS) cohort. We observed a maximum of 12,033 significant findings (p < 3.6 × 10−8) for BMI in a marginal linear regression EWAS. By contrast, a joint and conditional Bayesian penalized regression approach yielded 27 high-confidence associations with BMI. EpiScores trained in GS performed well in both Scottish and Singaporean test cohorts (Lothian Birth Cohort 1936 [LBC1936] and Health for Life in Singapore [HELIOS]). The EpiScores for BMI and total cholesterol performed best in HELIOS, explaining 20.8% and 7.1% of the variance in the measured traits, respectively. The corresponding results in LBC1936 were 14.4% and 3.2%, respectively. Differences were observed in HELIOS for body fat, where the EpiScore explained ∼9% of the variance in Chinese and Malay -subgroups but ∼3% in the Indian subgroup. The EpiScores also correlated with cognitive function in LBC1936 (standardized βrange: 0.08–0.12, false discovery rate p [pFDR] < 0.05). Accounting for the correlation structure across the methylome can vastly affect the number of lead findings in EWASs. The EpiScores of metabolic traits are broadly applicable across populations and can reflect differences in cognition.}, author = {Smith, Hannah M. and Ng, Hong Kiat and Moodie, Joanna E. and Gadd, Danni A. and Mccartney, Daniel L. and Bernabeu, Elena and Campbell, Archie and Redmond, Paul and Taylor, Adele and Page, Danielle and Corley, Janie and Harris, Sarah E. and Tay, Darwin and Deary, Ian J. and Evans, Kathryn L. and Robinson, Matthew Richard and Chambers, John C. and Loh, Marie and Cox, Simon R. and Marioni, Riccardo E. and Hillary, Robert F.}, issn = {1537-6605}, journal = {American Journal of Human Genetics}, number = {1}, pages = {106--115}, publisher = {Elsevier}, title = {{DNA methylation-based predictors of metabolic traits in Scottish and Singaporean cohorts}}, doi = {10.1016/j.ajhg.2024.11.012}, volume = {112}, year = {2025}, } @inbook{18765, abstract = {Mosaic Analysis with Double Markers (MADM) represents a mouse genetic approach coupling differential fluorescent labeling to genetic manipulations in dividing cells and their lineages. MADM uniquely enables the generation and visualization of individual control or homozygous mutant cells in a heterozygous genetic environment. Among its diverse applications, MADM has been used to dissect cell-autonomous gene functions important for cortical development and neural development in general. The high cellular resolution offered by MADM also permits the analysis of transcriptomic changes of individual cells upon genetic manipulations. In this chapter, we describe an experimental protocol combining the generation and isolation of MADM-labeled cells with downstream single-cell RNA-sequencing technologies to probe cell-type specific phenotypes due to genetic mutations at single-cell resolution.}, author = {Cheung, Giselle T and Pauler, Florian and Hippenmeyer, Simon}, booktitle = {Lineage Tracing}, editor = {Garcia-Marques, Jorge and Lee, Tzumin}, isbn = {9781071643099}, issn = {1940-6029}, pages = {139--151}, publisher = {Springer Nature}, title = {{Probing Cell-Type Specificity of Mutant Phenotype at Transcriptomic Level Using Mosaic Analysis with Double Markers (MADM)}}, doi = {10.1007/978-1-0716-4310-5_7}, volume = {2886}, year = {2025}, } @article{18778, abstract = {Transcription by RNA polymerase II (Pol II) can be repressed by noncoding RNA, including the human RNA Alu. However, the mechanism by which endogenous RNAs repress transcription remains unclear. Here we present cryogenic-electron microscopy structures of Pol II bound to Alu RNA, which reveal that Alu RNA mimics how DNA and RNA bind to Pol II during transcription elongation. Further, we show how distinct domains of the general transcription factor TFIIF control repressive activity. Together, we reveal how a noncoding RNA can regulate mammalian gene expression.}, author = {Tluckova, Katarina and Kaczmarek, Beata M and Testa Salmazo, Anita P and Bernecky, Carrie A}, issn = {1545-9985}, journal = {Nature Structural & Molecular Biology}, pages = {607--612}, publisher = {Springer Nature}, title = {{Mechanism of mammalian transcriptional repression by noncoding RNA}}, doi = {10.1038/s41594-024-01448-7}, volume = {32}, year = {2025}, } @article{18820, abstract = {Feature selection is essential in the analysis of molecular systems and many other fields, but several uncertainties remain: What is the optimal number of features for a simplified, interpretable model that retains essential information? How should features with different units be aligned, and how should their relative importance be weighted? Here, we introduce the Differentiable Information Imbalance (DII), an automated method to rank information content between sets of features. Using distances in a ground truth feature space, DII identifies a low-dimensional subset of features that best preserves these relationships. Each feature is scaled by a weight, which is optimized by minimizing the DII through gradient descent. This allows simultaneously performing unit alignment and relative importance scaling, while preserving interpretability. DII can also produce sparse solutions and determine the optimal size of the reduced feature space. We demonstrate the usefulness of this approach on two benchmark molecular problems: (1) identifying collective variables that describe conformations of a biomolecule, and (2) selecting features for training a machine-learning force field. These results show the potential of DII in addressing feature selection challenges and optimizing dimensionality in various applications. The method is available in the Python library DADApy.}, author = {Wild, Romina and Wodaczek, Felix and Del Tatto, Vittorio and Cheng, Bingqing and Laio, Alessandro}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Automatic feature selection and weighting in molecular systems using Differentiable Information Imbalance}}, doi = {10.1038/s41467-024-55449-7}, volume = {16}, year = {2025}, } @article{18821, abstract = {Even though the one-dimensional contact interaction requires no regularization, renormalization methods have been shown to improve the convergence of numerical calculations considerably. In this work, we compare and contrast these methods: “the running coupling constant” where the two-body ground-state energy is used as a renormalization condition, and two effective interaction approaches that include information about the ground as well as excited states. In particular, we calculate the energies and densities of few-fermion systems in a harmonic oscillator with the configuration-interaction method and compare the results based upon renormalized and bare interactions. We find that the use of the running coupling constant instead of the bare interaction improves convergence significantly. A comparison with an effective interaction, which is designed to reproduce the relative part of the energy spectrum of two particles, showed a similar improvement. The effective interaction provides an additional improvement if the center-of-mass excitations are included in the construction. Finally, we discuss the transformation of observables alongside the renormalization of the potential, and demonstrate that this might be an essential ingredient for accurate numerical calculations.}, author = {Brauneis, Fabian and Hammer, Hans Werner and Reimann, Stephanie M. and Volosniev, Artem}, issn = {2469-9934}, journal = {Physical Review A}, number = {1}, publisher = {American Physical Society}, title = {{Comparison of renormalized interactions using one-dimensional few-body systems as a testbed}}, doi = {10.1103/PhysRevA.111.013303}, volume = {111}, year = {2025}, } @article{18822, abstract = {Let N(X) be the number of integral zeros (mathematical equation). Works of Hooley and Heath-Brown imply (mathematical equation), if one assumes automorphy and grand Riemann hypothesis for certain Hasse–Weil L-functions. Assuming instead a natural large sieve inequality, we recover the same bound on N(X). This is part of a more general statement, for diagonal cubic forms in (mathematical equation) variables, where we allow approximations to Hasse–Weil L-functions.}, author = {Wang, Victor}, issn = {2041-7942}, journal = {Mathematika}, number = {1}, publisher = {London Mathematical Society}, title = {{Diagonal cubic forms and the large sieve}}, doi = {10.1112/mtk.70008}, volume = {71}, year = {2025}, } @article{18823, author = {Cao, Dechang and De Jaeger-Braet, Joke G}, issn = {1532-2548}, journal = {Plant Physiology}, number = {1}, publisher = {Oxford University Press}, title = {{Memory of maternal temperatures: DNA methylation alterations across generations}}, doi = {10.1093/plphys/kiae651}, volume = {197}, year = {2025}, } @misc{18837, abstract = {Super-resolution methods provide far better spatial resolution than the optical diffraction limit of about half the wavelength of light (∼200-300 nm). Nevertheless, they have yet to attain widespread use in plants, largely due to plants’ challenging optical properties. Expansion microscopy improves effective resolution by isotropically increasing the physical distances between sample structures while preserving relative spatial arrangements and clearing the sample. However, its application to plants has been hindered by the rigid, mechanically cohesive structure of plant tissues. Here, we report on whole-mount expansion microscopy of thale cress (Arabidopsis thaliana) root tissues (PlantEx), achieving a four-fold resolution increase over conventional microscopy. Our results highlight the microtubule cytoskeleton organization and interaction between molecularly defined cellular constituents. Combining PlantEx with stimulated emission depletion (STED) microscopy, we increase nanoscale resolution and visualize the complex organization of subcellular organelles from intact tissues by example of the densely packed COPI-coated vesicles associated with the Golgi apparatus and put these into a cellular structural context. Our results show that expansion microscopy can be applied to increase effective imaging resolution in Arabidopsis root specimens.}, author = {Danzl, Johann G and Kreuzinger, Caroline}, publisher = {Institute of Science and Technology Austria}, title = {{Research Data for the publication "Super-resolution expansion microscopy in plant roots"}}, doi = {10.15479/AT:ISTA:18837}, year = {2025}, } @article{18848, abstract = {Type II CRISPR endonucleases are widely used programmable genome editing tools. Recently, CRISPR-Cas systems with highly compact nucleases have been discovered, including Cas9d (a type II-D nuclease). Here, we report the cryo-EM structures of a Cas9d nuclease (747 amino acids in length) in multiple functional states, revealing a stepwise process of DNA targeting involving a conformational switch in a REC2 domain insertion. Our structures provide insights into the intricately folded guide RNA which acts as a structural scaffold to anchor small, flexible protein domains for DNA recognition. The sgRNA can be truncated by up to ~25% yet still retain activity in vivo. Using ancestral sequence reconstruction, we generated compact nucleases capable of efficient genome editing in mammalian cells. Collectively, our results provide mechanistic insights into the evolution and DNA targeting of diverse type II CRISPR-Cas systems, providing a blueprint for future re-engineering of minimal RNA-guided DNA endonucleases.}, author = {Ocampo, Rodrigo Fregoso and Bravo, Jack Peter Kelly and Dangerfield, Tyler L. and Nocedal, Isabel and Jirde, Samatar A. and Alexander, Lisa M. and Thomas, Nicole C. and Das, Anjali and Nielson, Sarah and Johnson, Kenneth A. and Brown, Christopher T. and Butterfield, Cristina N. and Goltsman, Daniela S.A. and Taylor, David W.}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{DNA targeting by compact Cas9d and its resurrected ancestor}}, doi = {10.1038/s41467-024-55573-4}, volume = {16}, year = {2025}, } @article{18849, abstract = {Many biological systems operate near the physical limits to their performance, suggesting that aspects of their behavior and underlying mechanisms could be derived from optimization principles. However, such principles have often been applied only in simplified models. Here, we explore a detailed mechanistic model of the gap gene network in the Drosophila embryo, optimizing its 50+ parameters to maximize the information that gene expression levels provide about nuclear positions. This optimization is conducted under realistic constraints, such as limits on the number of available molecules. Remarkably, the optimal networks we derive closely match the architecture and spatial gene expression profiles observed in the real organism. Our framework quantifies the tradeoffs involved in maximizing functional performance and allows for the exploration of alternative network configurations, addressing the question of which features are necessary and which are contingent. Our results suggest that multiple solutions to the optimization problem might exist across closely related organisms, offering insights into the evolution of gene regulatory networks.}, author = {Sokolowski, Thomas R and Gregor, Thomas and Bialek, William and Tkačik, Gašper}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {1}, publisher = {National Academy of Sciences}, title = {{Deriving a genetic regulatory network from an optimization principle}}, doi = {10.1073/pnas.2402925121}, volume = {122}, year = {2025}, } @article{18850, abstract = {Biophysical constraints limit the specificity with which transcription factors (TFs) can target regulatory DNA. While individual nontarget binding events may be low affinity, the sheer number of such interactions could present a challenge for gene regulation by degrading its precision or possibly leading to an erroneous induction state. Chromatin can prevent nontarget binding by rendering DNA physically inaccessible to TFs, at the cost of energy-consuming remodeling orchestrated by pioneer factors (PFs). Under what conditions and by how much can chromatin reduce regulatory errors on a global scale? We use a theoretical approach to compare two scenarios for gene regulation: one that relies on TF binding to free DNA alone and one that uses a combination of TFs and chromatin-regulating PFs to achieve desired gene expression patterns. We find, first, that chromatin effectively silences groups of genes that should be simultaneously OFF, thereby allowing more accurate graded control of expression for the remaining ON genes. Second, chromatin buffers the deleterious consequences of nontarget binding as the number of OFF genes grows, permitting a substantial expansion in regulatory complexity. Third, chromatin-based regulation productively co-opts nontarget TF binding for ON genes in order to establish a “leaky” baseline expression level, which targeted activator or repressor binding subsequently up- or down-modulates. Thus, on a global scale, using chromatin simultaneously alleviates pressure for high specificity of regulatory interactions and enables an increase in genome size with minimal impact on global expression error.}, author = {Perkins, Mindy Liu and Crocker, Justin and Tkačik, Gašper}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences}, number = {1}, publisher = {National Academy of Sciences}, title = {{Chromatin enables precise and scalable gene regulation with factors of limited specificity}}, doi = {10.1073/pnas.2411887121}, volume = {122}, year = {2025}, }