Biology subjects

Cheong, J.-H.

Publications and source records attributed to Cheong, J.-H..

At least 19 recordsLinked to original sources

bioRxiv2026

Kinetic gating by an iron sulfur chain modulates flavin radical-pair spin chemistry in mitochondrial Complex I

Mitochondrial Complex I generates reactive oxygen species at its flavin cofactor, where spin dependent reaction pathways have been proposed. Models of this chemistry treat the flavin oxygen radical pair in isolation, although the flavin is wired to a chain of eight iron sulfur clusters. Here we model the pair with this chain using the human Complex I structure and open quantum system models of spin coupling and electron transfer. In the simulated network, spin coherence decays rapidly along the chain, whereas proximal clusters alter the calculated radical-pair singlet yield. Their influence is kinetically gated: a downstream cluster affects the modelled yield when its electron-transfer rate competes with radical pair recombination, a threshold robust to driving force and to the transfer model. Modelling does set the sign: one directional spin hops predict suppression and inflate coherence transport, whereas charge resolved transfer drives the singlet yield towards its spin-randomized limit unless triplet recombination dominates. Detectable spin dependent effects in this framework require superoxide spin relaxation to be substantially slower than in free solution, a condition not yet established for Complex I.

biophysics↗

bioRxiv2026

Cancers relax selection on charge at the mitochondrial complex I quinone cavity

Mitochondrial complex I translocates protons through hydrated channels whose connectivity and electrostatics are both defined by structure, but whether they are distinctly constrained is unknown. From a 2.39 cryo-EM structure modelling 2,945 ordered waters, we built the proton wire of the seven mtDNA-encoded ND subunits and scored all 40,166 missense substitutions on two near-orthogonal axes (r = 0.17): electrostatic shift at proton-loading sites, and topological disruption of the wire. Across 858 germline variant sites, loading sites (0.51) and cut vertices (0.67) are both depleted. In tumours only loading sites are enriched (1.42 TCGA, 1.67 PCAWG, 1.29 MSK-IMPACT), a 3.06-fold difference tested as a wire class tissue-type interaction (P = 3.6 10-). It survives adjustment for conservation, burial and coverage, and is concentrated in ND1 within 15 of the quinone cavity, not spread along the proton path. Selection separates charge from connectivity, without establishing a fitness benefit.

biophysics↗

bioRxiv2026

Relaxed evolutionary constraints on mitochondrial electron-transfer-associated variants in human cancers

Mitochondrial electron transfer depends on quantum-mechanical coupling between redox cofactors, but its evolutionary constraints in cancer remain unclear. We combined the human complex III cryo-EM structure, Pathways calculations and Marcus theory to predict how missense substitutions in mitochondrial cytochrome b (MT-CYB), which coordinates the Q-cycle haem centres, affect electron-transfer kinetics. Comparing 524 somatic mutations from TCGA and PCAWG with 597 germline variant sites, we found that charge-changing substitutions near the haems were depleted in the germline (observed/expected, 0.12) but enriched in tumours (1.81). Greater predicted kinetic perturbations corresponded to stronger germline depletion and tumour enrichment, predominantly at low heteroplasmy and independently of tumour purity. Predicted kinetic effects correlated strongly with electrostatic perturbations (r = 0.94), precluding identification of tunnelling-specific selection. These findings support relaxed purifying selection on MT-CYB variants predicted to disrupt mitochondrial electron transfer during the evolution of diverse human cancers, without demonstrating adaptive benefits or selection on tunnelling itself.

genomics↗

bioRxiv2026

Delocalized DNA holes imprint mutation position in mismatch-repair-deficient cancers

One electron oxidation of DNA generates migrating holes that come to rest at guanine runs, a positional pattern of damage characterized in vitro but not shown to reach somatic mutation in human cancer. In mismatch repair deficient gastric, colorectal and endometrial tumours, we find G>T substitutions within guanine runs enriched at the 5' guanine (0.86~0.87) and depleted at the 3' guanine (0.05~0.08), specific to G>T and near identical across all three cancer types. The profile along runs of two to five guanines, including the flattening of the profile as runs lengthen, matches the charge density computed for a delocalized hole without fitting (r = 0.87~0.93); treating the transfer integral as the only free parameter returns 0.073~0.088 eV from four datasets: three tumour cohorts, and mismatch-repair-knockout cells grown without added damage that share no part of the tumour pipeline. A defined one electron oxidant reproduces the asymmetry in repair proficient cells, and the asymmetry is undiminished among clonal mutations, where oxidation introduced during library preparation cannot reach. Guanine ionization energy nonetheless does not predict the genomic distribution of C>A substitutions, in any oxidative stratum of non hypermutated tumours or in the reference signature attributed to reactive oxygen species, delimiting where this chemistry reaches the cancer mutation spectrum.

genomics↗

bioRxiv2026

Geometry derived Hamiltonian organization distinguishes recurrent biological Fe S architectures

Iron-sulfur (Fe-S) clusters are among the most ancient biological cofactors, yet the physical properties associated with the recurrent biological utilization of specific Fe-S architectures remain unclear. Here, we analyzed 2,404 experimentally resolved Fe-S clusters using an integrated framework combining structural geometry, geometry-derived effective-coupling network robustness, and coarse-grained open-system quantum transport simulations. We show that 4Fe-4S clusters occupy a compact and partially distinct region of structural-descriptor space characterized by low geometric distortion, elevated geometry-derived network robustness, and broad taxonomic representation within the available structural dataset. Geometry-derived coarse-grained effective Hamiltonian reconstruction and Lindblad simulations further showed architecture-dependent differences in Hamiltonian organization and simulated transport behavior under a common set of model assumptions. Together, these findings establish a hierarchical comparative framework linking Fe-S geometry, effective Hamiltonian organization, simulated open-system transport, and broad taxonomic recurrence, and suggest that geometry-derived transport organization may represent one physical property contributing to the recurrent biological utilization of Fe-S architectures.

biophysics↗

bioRxiv2026

Structure-defined amplification of spin-dependent radical-pair reactivity in mitochondrial complex I

Mitochondrial complex I generates reactive oxygen species (ROS), but whether radical pair spin dynamics shape these reactions is unknown. We combined cryo-electron microscopy-guided oxygen sampling with radical pair quantum dynamics to examine how the protein environment around flavin mononucleotide (FMN) shapes spin-dependent reaction outcomes. Sterically accessible oxygen positions clustered near FMN, and spin sensitivity concentrated in a narrow region about 3.3 angstroms away, where magnetic coupling between radicals is strong. This hotspot was robust across varying reaction rates, although its magnitude fell sharply with faster spin dephasing, implying observable effects require unusually slow dephasing. Magnetic sensitivity itself showed no sharp peak near FMN, rising instead to a plateau farther away, indicating the hotspot reflects accessibility rather than a localized maximum. Structural fluctuations produced greater yield variability within the hotspot, suggesting the FMN pocket amplifies small geometric changes into heterogeneous ROS outcomes, linking structure to spin-dependent chemistry in complex I.

biophysics↗

bioRxiv2026

Gene Program Negotiation Defines Cellular Identity in Single-Cell Transcriptomes

Single-cell transcriptomics has transformed the characterization of cellular heterogeneity by enabling systematic analysis of biological gene programs. However, existing computational approaches primarily quantify the activity of individual programs independently and therefore provide limited insight into how multiple simultaneously active programs collectively determine cellular identity. Here we present Gene Program Negotiation (GPN), a graph-based computational framework that models regulatory decision-making among concurrently active biological programs. GPN reconstructs cell-specific program interaction networks from local transcriptional neighborhoods and quantifies regulatory organization using the Gene Program Coherence Index (GPCI) together with measures of local regulatory conflict, program diversity, and dominance. These graph-derived properties enable the classification of individual cells into five regulatory decision states: Consensus, Competition, Negotiation, Dominance, and Low activity. Applying GPN to gastric cancer single-cell transcriptomes revealed that cells sharing the same dominant biological program frequently occupied distinct regulatory decision states, demonstrating that dominant program identity alone does not uniquely define cellular regulatory organization. Competition states consistently exhibited elevated local regulatory conflict and were preferentially enriched among transition-like cells, indicating that regulatory competition is closely associated with transcriptional plasticity. Independent validation using glioblastoma single-cell transcriptomes reproduced these regulatory patterns without modification of the computational framework, supporting the robustness and generalizability of the approach across biologically distinct malignancies. These findings establish regulatory negotiation as an additional layer of cellular organization beyond conventional gene-program activity analysis. By explicitly modeling interactions among simultaneously active biological programs, GPN provides a general computational framework for investigating regulatory coordination, cellular plasticity, and dynamic cell-state organization in single-cell transcriptomic data.

bioinformatics↗

bioRxiv2026

FateLimit quantifies the prediction horizon of cell fate

Single-cell technologies have enabled increasingly detailed reconstruction of developmental trajectories, yet a fundamental question remains unresolved: when does future cellular identity become predictable from a cells current molecular state? Existing approaches infer lineage relationships, transition probabilities or future transcriptional dynamics, but do not directly quantify the emergence of fate predictability during cellular state transitions. Here we present FateLimit, an information-theoretic framework for measuring the temporal dynamics of cell-fate predictability from single-cell omics data. FateLimit combines probabilistic fate assignment, fate entropy and mutual information to quantify how information about future cellular outcomes is encoded in present molecular states. We introduce two quantitative descriptors: the Fate Information Half-Life (FIHL), which measures the characteristic timescale of fate-information dynamics, and the Prediction Horizon (PH), defined as the earliest developmental stage at which observed fate predictability exceeds the 95th percentile of a permutation-derived null distribution. We applied FateLimit across developmental, lineage-tracing and reprogramming systems, including pancreatic endocrinogenesis, CellTag reprogramming, human hematopoiesis and zebrafish embryogenesis. Across all datasets, FateLimit identified significant fate information and reproducible prediction horizons that were robust to cell-state representation, lineage structure and biological context. Comparative analysis revealed that prediction horizons differ substantially among cellular lineages, indicating that distinct developmental programs acquire predictive information at different rates. FateLimit establishes a general framework for quantifying the predictability of future cellular identity from present molecular states. By transforming developmental trajectories into predictability landscapes, FateLimit enables systematic comparison of commitment dynamics across biological systems and establishes prediction horizons as a quantitative measure of cell-fate determination.

bioinformatics↗

bioRxiv2026

Leigh syndrome as a disorder of protein glass dynamics disrupting electron transport in mitochondrial Complex I

Leigh syndrome is the most common pediatric mitochondrial encephalopathy, yet the physical mechanisms linking diverse pathogenic mutations to respiratory-chain failure remain poorly understood. Here we show that Leigh syndrome mutations are not randomly distributed within human mitochondrial Complex I but are preferentially enriched near the electron-transfer axis connecting flavin mononucleotide and iron-sulfur cofactors. By integrating structural mutation mapping with residue-level free-volume analysis, packing-density measurements, and a protein glass index (PGI), we identify a distinct class of mutation-associated microenvironments characterized by reduced free volume, elevated packing density, and increased structural constraint. These protein-glass-like microenvironments were associated with elevated reorganization-energy proxies and increased transport vulnerability. Structure-informed Marcus analyses further identified a dominant bottleneck that was primarily associated with reduced electronic coupling arising from donor-acceptor separation, while local microenvironmental constraints further amplified transport sensitivity. Structure-informed Marcus analyses identify the emergence of a dominant kinetic bottleneck within the iron-sulfur cluster network, and a Lindblad-based open quantum transport model indicates that local microenvironmental perturbations can propagate into network-level transport efficiency across the Complex I redox chain. Notably, pathogenic mutations preferentially accumulate in structural neighborhoods that are intrinsically sensitive to electron-transfer perturbation, suggesting that disease-associated variants may amplify pre-existing transport vulnerabilities embedded within the protein architecture. Collectively, our findings suggest a structural-energetic link between mutation landscapes, local protein-glass-like organization, and mitochondrial electron transport. We propose that Leigh syndrome can be viewed, in part, through a protein-glass lens in which pathogenic mutations preferentially map to structural-energy landscapes surrounding redox cofactors that are predicted to be vulnerableto electron-transfer perturbations. This framework provides a physical perspective for understanding genotype-to-phenotype convergence in mitochondrial disease and identifies local protein-glass analogous microenvironments as previously unrecognized determinants of respiratory-chain dysfunction.

biophysics↗

bioRxiv2026

Information Geometry of Intracellular Compartment Coupling Reveals Transcriptomic State Transitions in Single Cells

Single-cell transcriptomic analyses typically characterize cellular states using gene-expression variability, dimensionality reduction, and trajectory inference. However, existing approaches provide limited insight into how transcriptomic information is organized across interacting intracellular compartments. Here we introduce Compartment Coupling Entropy (CCE), an information-geometric framework that quantifies the organization of transcriptomic coupling between spliced and unspliced RNA compartments. CCE constructs a cross-compartment coupling operator from compartment-resolved transcriptomic profiles and characterizes its singular-value spectrum using coupling entropy, effective coupling dimension, and coupling susceptibility. These metrics measure how transcriptomic information is distributed across coupling modes and provide a quantitative description of transcriptomic organization beyond conventional expression-based statistics. Applying CCE to pancreatic endocrine differentiation revealed substantial remodeling of coupling architecture along developmental trajectories. Coupling entropy and effective coupling dimension underwent transient collapse and re-expansion during lineage progression, while coupling susceptibility identified discrete intervals of rapid transcriptomic reorganization corresponding to candidate cell-state transition regimes. Across cell states, coupling entropy showed weak correspondence with classical mutual information, indicating that spectral coupling organization captures information not represented by conventional information-theoretic measures. An organization ratio and spectral excess information further quantified the divergence between classical and coupling-based descriptions of transcriptomic structure. Robustness analyses demonstrated stability of the framework under bootstrap resampling, gene subsampling, spectral truncation, and trajectory discretization. Application to an independent dentate gyrus developmental dataset revealed similar hierarchical coupling spectra and susceptibility-defined transition regimes, suggesting that transient reorganization of compartment-coupling architecture may represent a general feature of cellular state transitions. CCE provides a general methodology for quantifying the information geometry of intracellular transcriptomic organization and complements existing single-cell analytical approaches by revealing coupling architectures that are inaccessible to conventional expression-based analyses.

bioinformatics↗

bioRxiv2026

Quantum transport in mitochondrial complex I is governed by a conserved structural bottleneck

Electron transport in mitochondrial complex I is mediated by a chain of redox centers, yet how electrons traverse this network beyond the canonical pathway remains unclear. While prior models treat transport as a sequential process, they do not resolve whether alternative pathways contribute to functional electron flow. Here, we formulate electron transport as a continuous-time quantum walk on a structure-derived redox network and systematically map pathway-level electron flux inferred from quantum-walk dynamics across species. We identify a conserved structural bottleneck at the N5-N6a interface that suppresses direct electron transfer. Strikingly, quantum-walk flux analysis indicates that this bottleneck does not simply limit transport, but can redistribute electron flux into residue-mediated alternative pathways. Across species, these alternative routes support substantial flux and, in several cases, are comparable to or can exceed the canonical direct pathway, indicating a conserved mechanism of pathway-level flux redistribution. This behavior arises from geometric constraints encoded in protein structure and persists under environmental decoherence, demonstrating that architecture governs not only transport efficiency but also the organization of electron flow within the network. Together, our findings suggest a network-level organization of electron transport in complex I, in which a structurally encoded bottleneck reshapes flux through alternative pathways, consistent with a structurally encoded link between protein geometry and quantum transport behavior. We note that the bottleneck-dominated and flux-redistribution observations are not in tension: suppression of the direct N5-N6a step is precisely what redirects amplitude into the parallel residue-mediated routes.

biophysics↗

bioRxiv2026

Developmental plasticity of cancer-associated fibroblasts contributes to the malignant progression of gastric cancers

Cancer-associated fibroblasts are transcriptionally heterogeneous, yet how their reprogramming shapes gastric cancer progression remains unclear. Integrating single-cell and spatial transcriptomics, patient-derived fibroblast co-culture, and clinical cohorts, we identified a spatially organized continuum of extracellular matrix-producing fibroblasts. An inferred trajectory connected homeostatic ECMh through inflammatory-chemoattractive ECMi to tissue-remodeling ECMr, with increasing GLIS2 regulon activity and ECMr enrichment near the tumor-stroma interface. ECMr co-culture induced a non-EMT epithelial program characterized by coordinated laminin-332 subunit expression, hemidesmosome-associated genes, a matrix-remodeling protease profile, and reduced proliferative activity. Longitudinal imaging showed progressive cancer-cell elongation and positional displacement over the fibroblast layer. ECMr-associated GLIS2 regulon activity in resected primary tumors was associated with shorter peritoneal metastasis-free survival across two gastric cancer cohorts, with a similar association in colorectal cancer. A peritoneal metastasis recapitulated the corresponding stromal and epithelial organization. Together, these findings define an ECMr-centered stromal-epithelial wound-repair circuit linked to subsequent peritoneal dissemination.

cancer biology↗

bioRxiv2026

A Spin-Glass Metabolic Hamiltonian optimized by Quantum Annealing Reveals Thermodynamic Phases of Cancer Metabolism

Understanding why specific metabolic states become stable in cancer has remained a fundamental challenge, as current pathway-centric frameworks lack a unifying physical principle governing global metabolic organization. We introduce the Metabolic Spin-Glass (MSG) model, which represents cellular metabolism using a thermodynamically informed effective Hamiltonian that integrates reference reaction free energies, cofactor-mediated network couplings, and patient-specific transcriptomic fields within a frustrated many-body optimization framework. The Hamiltonian is formulated as a binary optimization problem and solved using hybrid quantum annealing. Embedding gastric cancer transcriptomes (n = 497) reveals that malignant phenotypes occupy distinct low-energy configurations within the effective metabolic landscape rather than representing isolated pathway perturbations. A thermodynamic order parameter stratifies patients into prognostically distinct subtypes independently of transcriptomic classification, suggesting clinically applicable non-redundant biomarkers. This work establishes a thermodynamically informed spin-glass energy-landscape framework for patient-specific characterization and stratification of cancer metabolic organization.

biophysics↗

bioRxiv2024

Deep Gaussian Process with Uncertainty Estimation for Microsatellite Instability and Immunotherapy Response Prediction Based on Histology

Determining tumor microsatellite status has significant clinical value because tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) respond well to immune check-point inhibitors (ICIs) and oftentimes not to chemotherapeutics. We propose MSI-SEER, a deep Gaussian process-based Bayesian model that analyzes H&E whole-slide images in weakly-supervised-learning to predict microsatellite status in gastric and colorectal cancers. We performed extensive validation using multiple large datasets comprised of patients from diverse racial backgrounds. MSI-SEER achieved state-of-the-art performance with MSI prediction, which was by integrating uncertainty prediction. We achieved high accuracy for predicting ICI responsiveness by combining tumor MSI status with stroma-to-tumor ratio. Finally, MSI-SEERs tile-level predictions revealed novel insights into the role of spatial distribution of MSI-H regions in the tumor microenvironment and ICI response.

bioinformatics↗

bioRxiv2024

Targeted Degradation of METTL3 Against Acute Myeloid Leukemia and Gastric Cancer.

Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancer types, either dependent or independent of its m6A methyl transferase activity. We have designed proteolysis-targeting chimeras (PROTACs) targeting METTL3 and identified KH12 as a potent METTL3 degrader. Treatment of KH12 on MOLM-13 cells causes more than 80% degradation of METTL3 with a half-maximal degradation concentration (DC50) of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition, KH12 reverses differentiation and possesses anti-proliferative effects surpassing the reported inhibitors in MOLM-13 cells. Furthermore, KH12 significantly suppresses the growth of various gastric cancer (GC) cells, where the m6A-independent activity of METTL3 plays a crucial role in tumorigenesis. The anti-GC effect of KH12 was further confirmed in patient-derived organoids (PDOs). This study highlights the therapeutic potential of targeted degradation of epitranscriptomic writer METTL3 as an anti-cancer strategy.

biochemistry↗

bioRxiv2023

Multi-omics Identification and Route-Specific Characterization of Metastasis-specific EMT Genes and Their Microenvironmental Interactions

BackgroundGastric cancer (GC) constitute a significant cause of cancer-related mortality worldwide, with metastatic patterns including hematogenous, peritoneal, and ovarian routes. Although GC gene expression patterns have been extensively researched, the metastasis-specific gene expression landscape remains largely unexplored. MethodsWe undertook a whole transcriptome sequencing analysis of 66 paired primary and metastatic (hematogenous, peritoneal, or ovarian) GC tumors from 14 patients. Public databases including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) was used for validation. Single-cell RNA sequencing (scRNA-seq) of four ascites from serosa positive GC patients and five primary tumors by layer (superficial and deep) were analyzed. ResultsThrough differential expression analysis between paired primary and metastatic tumors by routes identified 122 unique metastasis-specific epithelial-mesenchymal transition (msEMT) genes. These genes demonstrated varying expression patterns depending on the metastatic route, suggesting route-specific molecular mechanisms in GC metastasis. High expression of msEMT genes in primary tumors was associated with more frequent CDH1 mutations, the genomically stable subtype, and poor prognosis in TCGA GC cohort. This association was further corroborated by poor prognosis and high predictive performance for peritoneal/ovarian recurrence in two independent cohorts (GSE66229; n=300, GSE84437; n=433). scRNA-seq analysis of five primary tumors (GSE167297) and four independent ascites samples from GC patients revealed that msEMT genes were predominantly expressed in diverse fibroblast sub-populations, rather than cancer cells. ConclusionsThis study illuminates the route-specific mechanisms and underlines the significance of msEMT genes and cancer-associated fibroblasts in peritoneal metastasis of GC.

genomics↗

bioRxiv2023

Acquired epithelial WNT secretion drives niche independence of developing gastric cancer

Recent studies have shed light on the signaling pathways required for gastric tissue maintenance and how aberrations in these key pathways lead to gastric cancer development. Although it has been shown that the WNT pathway is important for gastric epithelial homeostasis, the identity and source of the responsible canonical WNT ligands remain unknown. Furthermore, it is unclear how gastric cancer acquires WNT niche independence - an important early step in tumorigenesis. Using human and mouse gastric organoids and in vivo mouse models, we found that mesenchymal WNT2B and WNT7B maintain gastric epithelium in homeostasis. Next, mouse genetic studies and single-cell multi-omics analyses revealed that activation of MAPK signaling induces secretion of WNT7B in the epithelium itself. We further confirmed that in human gastric cancer, MAPK pathway activation through HER2 overexpression or copy number gains of WNT2 confers WNT independence. Importantly, the epithelium-intrinsic WNT expression could be therapeutically inhibited. Taken together, our results reveal that normal gastric epithelial turnover relies on WNT ligands secreted by niche mesenchymal cells, while transformation involves acquisition of a WNT secretory phenotype in the epithelium - representing a potential target for therapeutic interventions.

cancer biology↗

bioRxiv2023

Serum albumin maintains Wnt water-solubility and activity

Wnt proteins regulate adult tissue homeostasis and repair by driving stem cell self-renewal and differentiation. High-performance Wnt preparations have enormous therapeutic potential, especially alongside various stem cell technologies. Currently, most of these Wnt preparations contain FBS or the detergent CHAPS to maintain Wnt solubility and activity. Recently, afamin was identified as a serum factor that solubilizes Wnt3a in conditioned media (CM), obviating the requirement for animal sera. Here, we report serum albumin (SA) is required for afamin-mediated solubilization of Wnt3a in CM. Moreover, SA-mediated solubilization of purified Wnt3a in tubes does not require afamin. This means conventional CHAPS-Wnt3a preparations can be modified into SA-purified Wnt3a (SA-pWnt3a) preparations by exchanging CHAPS for SA through dialysis. SA-pWnt3a preparations effectively promote the growth of human stem cell organoids. These data suggest SA as a physiological factor for maintaining Wnt3a activity in therapeutic applications.

biochemistry↗