Biology subjects

Feng, C.

Publications and source records attributed to Feng, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Ethylene receptors are functionally conserved in calcium permeability across the green lineage

The gaseous hormone ethylene plays a key role in regulating plant growth and stress responses. Although Ca{superscript 2} has long been implicated in ethylene signaling, the identity of molecules controlling Ca{superscript 2} permeability involved has remained elusive. Here we show that Arabidopsis ethylene receptors ETR1 and ERS1 are Ca2+ permeable, and that ETR1 mediates ethylene-induced cytosolic Ca2+ increase and regulates hypocotyl elongation. Homologs of ETR1 from eight land plant and algal species also exhibit Ca{superscript 2} permeability, suggesting an evolutionarily conserved function. We further demonstrate ethylene enhances the Ca2+ permeability of ETR1 and its homologue from the charophyte Klebsormidium flaccidum. These findings uncover a previously unrecognized but conserved role of ethylene receptors in Ca{superscript 2} permeability regulation in the green lineage, with broad implications for Ca{superscript 2} signaling in plant development and environmental adaptation.

plant biology↗

bioRxiv2025

Tubulin autoregulation factors SCAPER and TTC5 recruit γ-tubulin to non-centrosomal MTOCs for neuronal microtubule nucleation and axon regeneration

Neuronal function and survival depend on highly stereotyped non-centrosomal microtubule (MT) arrays. How these arrays form remains poorly understood. Here we identified a role for SCAPER and TTC5, two factors previously implicated in tubulin mRNA autoregulation, in controlling neuronal MT content through {gamma}-tubulin-dependent nucleation. In C. elegans neurons, loss of scpr-1, ttc-5, or both reduced MT numbers to a similar degree as depletion of {gamma}-tubulin, the main MT nucleator. Using conditional single-cell degradation alleles and endogenous tagging, we find that {gamma}-tubulin nucleates MTs in the neuronal cell body from endosomal puncta, and that scpr-1 and ttc-5 are required to recruit {gamma}-tubulin to these structures. SCPR-1 is also instructive, as its overexpression drastically increases {gamma}-tubulin levels and enhances MT density. We propose that these mechanisms are conserved since human SCAPER rescues C. elegans mutants, and SCAPER knockdown in rat hippocampal neurons reduces both {gamma}-tubulin clustering at presynaptic sites and activity-dependent synaptic MT nucleation. Finally, while scpr-1, ttc-5, and{gamma} -tubulin are not required for developmental axon elongation, they are essential for regeneration, where SCPR-1 directs {gamma}-tubulin to the growth cone to facilitate regrowth following injury. These findings reveal mechanisms governing neuronal cytoskeleton assembly and function, and suggest potential crosstalk between tubulin autoregulation and microtubule nucleation.

cell biology↗

bioRxiv2025

Progenitor T cells drive chronic pulmonary type 2 inflammation

Type 2 inflammation unfolds over time and is coordinated by remarkably durable CD4+ Th2 cell responses, standing in contrast to the collapse of adaptive immunity seen in chronic infection and malignancy. In experimental models, short-lived Th2 effector cells and type 2 innate lymphocytes (ILC2) contribute to acute type 2 inflammation, yet the cellular architecture that drives chronic type 2 inflammation and prevents exhaustion remains poorly understood. To define the Th2 landscape in chronic type 2 inflammation, we established a mouse model of long-term pulmonary allergen exposure and found that type 2 inflammation was broadly sustained over at least 4 months despite chronic stimulation. Th2 cells in the lung parenchyma during chronic inflammation were distinct from acute inflammation and resting memory phases, and included an expanded T cell factor-1 (TCF1)-expressing progenitor-like Th2 population. Tissue Th2 progenitors were absent in the nose and in helminth infections, suggesting that type 2 immunopathology is context-specific. Transcriptomic deconstruction of acute and chronic pulmonary Th2 responses defined divergent effector programs as well as the transcriptional signature of a tissue Th2 memory population that resembled human Th2 progenitors. Integrated transcriptomic analysis comparing type 2 inflammation to chronic viral infection revealed a distinct stemness module underlying chronic Th2 inflammation that was separable from a common core memory module. In vivo, lung Th2 progenitors coupled self-renewal with effector cell differentiation and could be sustained for weeks without antigen persistence or contribution from the lymph node. Maintenance of Th2 progenitors was partially dependent on lung parenchymal B cells and associated with bronchus-associated lymphoid tissue formation. Moreover, Th2 progenitors, in contrast to Th2 effectors and ILC2s, were sufficient to both initiate and sustain type 2 inflammation. Thus, we define tissue Th2 progenitors as a distinct cellular state that arises during chronic type 2 inflammation and establish the central role of these cells in maintaining the architecture of Th2 responses over time.

immunology↗

bioRxiv2025

Evolutionary patterns and repeated adaptive strategies of deep-sea anemones

Sea anemones occupy the full depth of the oceans, yet their evolutionary patterns and adaptive strategies to the enigmatic deep sea have remained contentious and poorly resolved. Here, we assemble genomes (n = 13) and transcriptomes for 15 species collected between 432 and 6,000 m and integrate them with all publicly available actiniarian data. Phylogenomic analyses reveal a mosaic topology among deep-sea and shallow-water clades. Using a novel framework that contrasts convergent gene-loss patterns, we show that a large number of light-associated gene families-- including the complete circadian toolkit--were independently deleted after lineages entered the aphotic realm, whereas comparable loss in shallow taxa is negligible, providing decisive support for a shallow-water origin followed by multiple descents. Intriguingly, some deep-sea lineages further streamline energy budgets by recurrent loss or pseudogenisation of key meiotic genes (e.g., Meiosin, Ythdc2, Spo11, Rad21, Mlh3), indicating a shift towards asexual reproduction. Despite this extensive genomic erosion, deep-sea anemones exhibit sophisticated molecular tuning: specific amino-acid substitutions enhance protein stability and activity under deep-sea conditions, while selective expansions of gene families related to neural excitability, membrane systems, etc., likely mitigate the suppressive environmental effects on vital physiological processes. Enzyme activity assays in the yeast system confirm that the deep-sea variants exhibit superior activity and enhanced growth at 4{degrees}C. These results define a "loss-optimization-innovation" triad that underlies bathymetric adaptations and may apply to other deep-sea fauna worldwide.

evolutionary biology↗

bioRxiv2025

HPInet: Interpretable prediction of Host-Pathogen protein-protein Interactions using a transformer-based neural network

Gram-negative bacteria utilize a series of secretion systems (T1SS-T10SS) to deliver secreted effector proteins (T1SE-T10SE) into host cells, leading to infections and diseases. Understanding the interactions between these effector proteins and host proteins is crucial for unraveling the pathogenic mechanisms of bacterial pathogens. Despite advancements in sequencing technologies that have significantly enhanced our knowledge of effector protein diversity and structure, the molecular mechanisms underlying their interactions with human host proteins remain unclear. Experimental approaches to validate these interactions are labor-intensive, time-consuming, and insufficient to comprehensively map the extensive effector-host protein interaction (PPI) network. Additionally, specialized computational tools for predicting these interactions remain scarce. To address this gap, we developed HPInet, a transformer-based deep learning model for predicting interactions between bacterial effector proteins and human host proteins. HPInet introduces convolutional layers and global response normalization (GRN) into the feed-forward network (FFN) of the transformer architecture, enhancing the extraction of local sequence features. Compared to existing state-of-the-art methods, HPInet significantly improves prediction performance, increasing accuracy from 0.502 to 0.891 and boosting sensitivity by 35.3%. Furthermore, by leveraging the models attention mechanism, HPInet identifies critical residues at interaction sites, demonstrating its capability to capture local structural features of PPI sites solely from sequence information. To facilitate its application in research, HPInet has been implemented as a freely accessible web server available at https://bis.zju.edu.cn/hpinet. This platform provides a powerful and interpretable tool for studying effector-host protein interactions, offering valuable insights into bacterial pathogenesis and potential therapeutic targets.

bioinformatics↗

bioRxiv2025

Repulsive vs. Attractive Crowding Distinctly Regulate TDP-43 Condensates through Region-Specific Structural Dynamic

TAR DNA-binding protein 43 (TDP-43) is crucial for RNA processing and nucleocytoplasmic transport, and its pathological aggregation is a hallmark of neurodegenerative disorders such as amyotrophic lateral sclerosis and frontotemporal dementia. The intrinsically disordered, prion-like C-terminal domain (CTD) of TDP-43 drives its liquid-liquid phase separation (LLPS), a process fundamental to both normal cellular function and disease-associated aggregation. Using coarse-grained molecular simulations, we systematically explored how distinct macromolecular crowding environments, including repulsive (steric) and attractive (interaction-based) crowding conditions, influence the phase behavior and internal organization of TDP-43 CTD condensates. Our findings reveal that both repulsive and attractive crowders maintain strong correlations between single-chain compaction, dimerization propensity, and macroscopic phase separation, yet operate via distinct physical mechanisms: repulsive crowders drive condensation through volume-exclusion-mediated entropic stabilization, while attractive crowders modulate condensate formation via competitive enthalpic interactions. Spatial structural analysis identifies a robust region-specific internal architecture, with -helices enriched at the condensate core and aligned parallel to the interface, and intrinsically disordered regions (IDRs) preferentially localized near the condensate surface in orientations nearly perpendicular to the interface. Dynamically, -helical regions form strong yet transient interaction hubs, whereas IDRs establish weaker but more persistent contacts, thereby maintaining structural fluidity. Collectively, our results uncover a regulatory principle by which macromolecular crowding modulates TDP-43 condensation through distinct entropic and enthalpic contributions, offering key mechanistic insights into condensate formation and dysregulation relevant to neurodegenerative diseases.

biophysics↗

bioRxiv2025

Population-specific brain charts reveal Chinese-Western differences in neurodevelopmental trajectories

Human brain charts provide unprecedented opportunities for decoding neurodevelopmental milestones and establishing clinical benchmarks for precision brain medicine 1-7. However, current lifespan brain charts are primarily derived from European and North American cohorts, with Asian populations severely underrepresented. Here, we present the first population-specific brain charts for China, developed through the Chinese Lifespan Brain Mapping Consortium (Phase I) using neuroimaging data from 43,037 participants (aged 0-100 years) across 384 sites nationwide. We establish the lifespan normative trajectories for 296 structural brain phenotypes, encompassing global, subcortical, and cortical measures. Cross-population comparisons with Western brain charts (based on data from 56,339 participants aged 0-100 years) reveal distinct neurodevelopmental patterns in the Chinese population, including prolonged cortical and subcortical maturation, accelerated cerebellar growth, and earlier development of sensorimotor regions relative to paralimbic regions. Crucially, these Chinese-specific charts outperform Western-derived models in predicting healthy brain phenotypes and detecting pathological deviations in Chinese clinical cohorts. These findings highlight the urgent need for diverse, population-representative brain charts to advance equitable precision neuroscience and improve clinical validity across populations.

neuroscience↗

bioRxiv2025

Dynamics of mesoscale brain network during decision-making learning revealed by chronic, large-scale single-unit recording

Associating unfamiliar stimuli with appropriate behavior through experience is crucial for survival. While task-relevant information was found to be distributed across multiple brain regions, how regional nodes in this distributed network reorganize their functional interactions throughout learning remains to be elucidated. Here, we performed chronic, large-scale single-unit recording across 10 cortical and subcortical regions using ultra-flexible microelectrode arrays in mice performing a visual decision-making task and tracked mesoscale functional network dynamics throughout learning. Task learning reshaped interregional functional connectivity, leading to the emergence of a subnetwork involving visual and frontal regions during the acquisition of correct No-Go responses. This reorganization was accompanied by a more widespread representation of visual stimulus across regions, and a regions network rank strongly predicted its peak timing of visual information encoding. Together, our findings revealed that mesoscale networks undergo dynamic restructuring during learning, with functional connectivity ranks influencing the propagation of sensory information across the network.

neuroscience↗

bioRxiv2025

Senescent mast cells contribute to the progression of benign prostatic hyperplasia via SCF/c-KIT mediated endothelial-mesenchymal transition

Benign prostatic hyperplasia (BPH) is a common age-associated urological condition characterized by stromal expansion, but its cellular origins and regulatory mechanisms remain unclear. In this study, we identified endothelial-to-mesenchymal transition (EndMT) as a contributor to stromal cell accumulation in BPH. Using single-cell transcriptomic analysis, endothelial lineage tracing in mice, and validation in human samples, we showed that senescence-associated mast cells increased the expression of vascular endothelial growth factor A (VEGFA) and transforming growth factor-beta 1 (TGF-{beta}1) through the stem cell factor (SCF)/c-KIT-MAPK-JUND signaling pathway, thereby inducing EndMT in endothelial progenitor cells. Stromal fibroblasts express SCF, promoting mast cell activation and establishing a feedback loop that supports continued stromal proliferation. Intriguingly, inhibition of mast cell activation reduces EndMT and attenuates prostate enlargement in vivo. Thus, these findings revealed a senescence-linked immune-stromal interaction in the aging prostate and identify potential targets for therapeutic intervention in BPH.

cell biology↗

bioRxiv2025

TIP-seq: A Single-cell Multiomics Approach for Simultaneous Transcriptome and Intracellular Protein Profiling

Single-cell multiomics technologies have significantly advanced our understanding of cellular heterogeneity; however, the concurrent profiling of mRNA transcripts and target proteins continues to pose a substantial challenge. To bridge the gap between single-cell sequencing and proteomic methods, we developed an innovative single-cell multiomics methodology, termed TIP-seq, which facilitates the simultaneous profiling of the transcriptome and intracellular proteins without prior cell manipulation. In TIP-seq, microfluidic technology is leveraged to integrate oligonucleotide-labeled antibodies with hydrogel beads, allowing for the capture of mRNAs and proteins from individual cells within droplets, thereby enabling high-throughput and precise dual-omics data acquisition. When applied to lung cell lines and non-small cell lung cancer (NSCLC) tissues, TIP-seq analysis revealed notable cellular heterogeneity and molecular dynamics, emphasizing the distinct immune cell interactions within NSCLC tissues. Key immune checkpoint interactions in NSCLC, such as SPP1-CD44, NECTIN2-TIGIT, and NECTIN2-CTLA4, along with functional alterations in tumor-associated dendritic cells (DCs) and T cells, were identified via TIP-seq, underscoring their pivotal roles in mediating immune suppression within the tumor microenvironment. Collectively, TIP-seq represents a powerful methodology for identifying novel therapeutic targets and biomarkers, thereby holding significant potential for the advancement of precision medicine in the treatment of lung cancer and other complex diseases.

biochemistry↗

bioRxiv2025

Neurocomputational Mechanisms Linking Future Interaction Prospects to Reactive and Proactive Costly Punishment

Costly punishment within social bonds manifests as both reactive penalties for transgressions and proactive sanctions against fair behaviors, yet a unified neurocomputational framework remains elusive. Combining neuroimaging and computational modeling, this study examined how future interaction prospects--a key element of social bonds--modulate reactive and proactive punishment. Participants acted as second- or third-party punishers, responding to allocation offers from individuals with or without future interactions. Results showed that participants imposed harsher punishment on both fair and unfair offers from individuals they did not expect to interact with, aligning with lower self-reported social closeness. Heightened provocation sensitivity, reflected in dorsal anterior cingulate cortex activity, drove the increased reactive punishment toward wrongdoers without future interactions, whereas punishment of future-interacting transgressors was associated with enhanced dorsolateral and dorsomedial prefrontal cortex (dlPFC, dmPFC) activity. A stronger preference for relative advantage and reduced harm sensitivity, linked to dlPFC and temporoparietal junction activity, mediated greater proactive punishment towards non-future-interacting individuals. Moreover, proactive punishment and underlying neurocognitive processes followed a collective retaliation pattern, increasing after unfair (vs. fair) behavior from another non-future-interacting individual. These findings establish a unified neurocomputational framework for understanding how future interaction prospects regulate costly punishment, integrating reactive and proactive motives within social bonds.

neuroscience↗

bioRxiv2025

Sequential Amino Acid Mutagenesis-Driven De Novo Evolution of Adenine Deaminases Enables Efficient In Vivo Base Editing in Primate

Base editing allows for the precise modification of genetic information, providing new avenues for treating diseases1. The adenine base editor ABE8e is currently the most efficient and widely used tool for adenine base editing. ABE8e was developed through multiple rounds of directed evolution of Escherichia coli tRNA adenine deaminase, including phage-assisted continuous evolution (PACE)2,3. While PACE is highly effective, it is a complex system that poses challenges for implementation4. Despite its high efficiency, ABE8e is associated with limitations such as relatively higher bystander editing effects and elevated off-target activity5, which need to be addressed to further enhance its precision and safety. Here, we developed a novel method for the de novo discovery of evolved ABE components, particularly adenine deaminases. This process involves identifying candidate proteins through AI-based structural prediction and clustering, followed by the enhancement of deaminase editing activity through screening libraries created by sequential amino acid saturation mutagenesis. This evolutionary strategy simplifies the approach by employing saturation mutagenesis libraries tailored to specific segments, thereby enabling exploration of an expanded sequence space and increasing the likelihood of discovering adenine deaminases with superior capabilities. The newly developed hpABE5.20 here demonstrates a more refined editing window, reduced DNA off-target effects that are both sgRNA-dependent and -independent, and minimized RNA off-target activity, while maintaining robust editing efficiency relative to ABE8e. Furthermore, hpABE5.20 has been successfully applied for precise and effective therapeutic adenine base editing in cellular disease models, humanized mice, and non-human primates.

bioengineering↗

bioRxiv2025

From cognition to compensation: Neurocomputational mechanisms of guilt-driven and shame-driven altruistic behavior

Guilt and shame are key moral emotions that influence mental health and regulate social behavior. Although prior research has examined the psychological and neural correlates of these emotions, the cognitive antecedents that trigger them, as well as their transformation into social behavior, remain insufficiently understood. In this study, we developed a novel task to investigate how two crucial cognitive antecedents, harm and responsibility, elicit guilt and shame, and how these emotions subsequently drive compensatory behavior, by combining functional magnetic resonance imaging (fMRI) with computational modeling. Behaviorally, we found that harm had a stronger impact on guilt than on shame, whereas responsibility had a stronger impact on shame than guilt, which supports the functionalist theory of emotion. Moreover, compared to shame, guilt exerted a greater effect on compensation. Computational modeling results indicated that the integration of harm and responsibility by individuals is consistent with the phenomenon of responsibility diffusion. The fMRI results revealed that brain regions associated with inequity representation (posterior insula) and value computation (striatum) encode this integrated measure. Furthermore, individual differences in responsibility-driven shame sensitivity were associated with activity in theory-of-mind regions (temporoparietal junction and superior temporal sulcus). Guilt- and shame-driven compensatory behavior recruited distinct neural substrates, with shame-driven compensatory sensitivity being more strongly linked to activity in the lateral prefrontal cortex, a region implicated in cognitive control. Our findings provide computational, algorithmic, and neural accounts of guilt and shame.

neuroscience↗

bioRxiv2025

Neural signature underlying the effect of intranasal vasopressin on emotional responses to spontaneous social comparison

Vasopressin, a key molecular regulator of social behavior, is implicated in promoting self-protective responses to threats against physical safety and resources. However, its role in defending against self-view threats--common in social interactions and critical to well-being--remains unclear. This study investigates the neural mechanisms through which vasopressin modulates self-protective responses to spontaneous social comparison. In a double-blind, placebo-controlled neuroimaging experiment, participants rated their satisfaction with social evaluations and monetary outcomes assigned to a stranger, friend, or themselves. Compared to placebo, vasopressin selectively intensified contrastive emotional responses to social evaluations of the stranger, decreasing satisfaction with positive evaluations and increasing satisfaction with negative evaluations, relative to those of the self or friend. At the neural level, vasopressin reduced the distinctions between the stranger and the self/friend in the medial prefrontal cortex activity, multivariate response patterns, and functional connectivity with the temporoparietal junction and precuneus, with this effect being especially pronounced among socially dominant individuals. These converging neuroimaging findings support the hypothesis that vasopressin alters the neural representation of the stranger, shifting it from a socially irrelevant figure under placebo to a psychologically salient competitor, thereby triggering self-protective emotional processes. These findings elucidate novel neuropsychological mechanisms through which vasopressin amplifies emotional defense against social threats and offer insights into potential clinical applications for psychiatric conditions characterized by impaired self-protection.

neuroscience↗

bioRxiv2025

AWmeta empowers adaptively-weighted transcriptomic meta-analysis

Transcriptomic meta-analysis enhances biological veracity and reproducibility by integrating diverse studies, yet prevailing P-value or effect-size integration approaches exhibit limited power to resolve subtle signatures. We present AWmeta, an adaptively-weighted framework that unifies both paradigms. Benchmarking across 35 Parkinsons and Crohns disease datasets spanning diverse tissues and adaptively down-weighting underpowered studies, AWmeta yields higher-fidelity differentially expressed genes (DEGs) with markedly reduced false positives and establishes superior gene differential quantification convergence at both gene and study levels over state-of-the-art random-effects model (REM) and original studies. AWmeta requires fewer samples and DEGs from original studies to achieve substantial gene differential estimates, lowering experimental costs. We demonstrate AWmetas remarkable stability and robustness against external and internal perturbations. Crucially, AWmeta prioritizes disease tissue-specific mechanisms with higher functional coherence than those from REM and original studies. By bridging statistical rigor with mechanistic interpretability, AWmeta harmonizes heterogeneous transcriptomic data into actionable insights, serving as a transformative tool for precision transcriptomic integration.

bioinformatics↗

bioRxiv2025

DNA Actively Regulates the "Safety-Belt" Dynamics of Condensin during Loop Extrusion

Condensin, a protein complex of the SMC (Structural Maintenance of Chromosomes) family, is essential for genome folding through its active DNA loop extrusion activity. Condensin contains a binding interface between its Ycg1 (HEAT-repeat) and Brn1 (kleisin) subunits that acts like a "safety belt" to trap DNA and prevent its dissociation during loop extrusion. The entrapment of DNA within the binding pocket of the SMC complex is crucial for ATPase activity and the asymmetric loop extrusion. However, the molecular mechanism underlying DNA entrapment remains unclear, hindering our understanding of how condensin functions at a molecular level. Here, we employ multiscale molecular dynamics simulations to reveal how DNA actively modulates condensins safety-belt dynamics. Using all-atom simulations combined with AlphaFold3 predictions, we demonstrate that DNA binding markedly stabilizes the condensin safety belt, facilitating loop extrusion progression. Coarse-grained simulations capture the entire DNA entrapment process, highlighting an active regulatory role of DNA: DNA positioned outside the safety belt triggers its opening, whereas DNA within promotes closure, enhancing complex stability. Kinetic analyses further reveal that the rate-limiting step in DNA entrapment depends critically on the tightness of the safety belt. A loose safety belt makes the stable closure of its "latch" and "buckle" components rate-limiting, whereas a tighter safety belt shifts the barrier to initial DNA entry. Additionally, we find that latch-buckle interaction strength regulates condensins sliding motion along DNA. Our findings provide a comprehensive molecular framework illustrating how DNA actively guides condensins safety-belt dynamics, substantially advancing our mechanistic understanding of chromosome loop extrusion.

biophysics↗

bioRxiv2025

Tissue-wide profiling of human lungs reveals spatial sequestration of macrophages in tuberculosis

The immune response to human tuberculosis (TB), particularly in the context of complex lung pathology, remains incompletely understood. Here, we employed whole-slide spatial proteomics to map immune cell organization in TB-affected human lung tissues. Our analysis revealed pronounced spatial segregation of major immune cell populations in non-necrotizing TB lesions. At the tissue level, macrophages and lymphocytes formed distinct cellular communities associated with specific pathological features. At the lesion level, macrophages and B cells showed an inverse relationship in both abundance and spatial distribution. Proinflammatory T cells preferentially accumulated in macrophage-rich lesions but remained largely separated from macrophages. Interestingly, lesions exhibiting clear segregation between T cells and macrophages were more common in subclinical TB than in active disease. These findings suggest that spatial isolation of macrophages from effector lymphocytes may help temper inflammation and potentially prevent lesion progression to necrosis, while also enabling immune evasion by Mycobacterium tuberculosis. One Sentence SummaryXiao et al. reveal spatial segregation of immune cells in TB-lung tissue and link the microenvironmental dynamics to disease states of tuberculosis.

immunology↗

bioRxiv2025

(A)symmetry in the Allele-Specific Chromosomal Structural Dynamics during Embryogenesis

Embryonic stem cells (ESCs) lie at the heart of regenerative medicine and hold significant potential for treating various diseases. Understanding how the transcriptional landscape of ESCs is established during embryogenesis is therefore pivotal for deciphering the origins of life and advancing therapeutic strategies. Given the intrinsic connection between genome structure and function, chromosomal structural organizations during embryogenesis play a vital role in shaping gene expression patterns in ESCs. In this study, we employed a data-driven model and non-equilibrium molecular dynamics simulations to quantify large-scale chromosomal structural dynamics during embryogenesis. We focused on allelic differences and their impact on the interplay between chromosomal structure, dynamics, and function. Our results reveal that higher-order chromosomal structure, such as compartments and topologically associated domains (TADs), follow allele-symmetric developmental pathways, whereas the overall geometrical structures of chromosomes exhibit allele asymmetry, with the paternal and maternal chromosome undergoing monotonic and non-monotonic compactions, respectively. Despite these differences, the spatial distribution of chromosomal loci, particularly those rich in genes, adapts in an allele-symmetric manner. We propose that these chromosomal structural organizations during embryogenesis are intricately linked with epigenetic modifications and likely contribute to the transition from totipotency to pluripotency. Moreover, our findings suggest that allele asymmetry in chromosome structural dynamics during embryogenesis arises from long-range interactions, while short-range structures, particularly TADs, promote allele symmetry, a process associated with zygotic genome activation (ZGA). Overall, our findings provide theoretical insights into the dynamic establishment of the ESC genome during embryogenesis from the chromosomal structure perspective, and potentially lay the groundwork for further applications in the field.

biophysics↗