Biology subjects

Xiang, S.

Publications and source records attributed to Xiang, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Cooperative IDR-folded domain interplay governs HP1α phase separation and underlies biphasic regulation by pathogenic poly-PR

HP1 undergoes liquid-liquid phase separation (LLPS), yet the prevailing model, which attributes condensation almost entirely to intrinsically disordered regions (IDRs), leaves the role of its folded domains unresolved. Using solution and solid-state NMR, we show that HP1 LLPS is instead governed by reciprocal interplay between IDRs and folded domains. Within the condensed phase, solid-state NMR reveals a dynamic hierarchy: the chromoshadow domain (CSD) assembles into polymorphic oligomers that form rigid cores, while the phosphorylation sites on the N-terminal extension (NTE) remain highly mobile, challenging their proposed role as stable multivalent hubs. Phosphorylation of the NTE instead promotes LLPS primarily by increasing local rigidity and releasing the NTE from the chromodomain (CD) to relieve autoinhibition, with electrostatic charge contributing secondarily. The C-terminal extension (CTE) suppresses phase separation through two routes: weakening the association between the hinge region (HR) and the CSD, and inhibiting interactions between CSD dimers. ALS-associated poly-PR targets this network at the NTE and exerts concentration-dependent biphasic regulation, promoting LLPS at low concentrations via multivalent bridging and dissolving condensates at high concentrations via saturation, a switch recapitulated in cells and in mouse brain. These findings reframe HP1 condensation from an IDR-driven process to one cooperatively governed by IDR-folded domain interplay.

biochemistry↗

bioRxiv2026

Sequence-encoded H2A.Z nucleosome dynamics control DNA unwrapping and SUV420H1 recognition

H2A.Z and canonical H2A adopt nearly identical nucleosomal folds, yet their distinct chromatin functions are not captured by static structural analysis. Using fast magic-angle spinning 1H-detected solid-state NMR, we show that H2A.Z possesses enhanced backbone flexibility in the L1 loop and the 2-L2 region (M2) relative to H2A. Chimeric segment-swapping demonstrates that these dynamic signatures are locally sequence-encoded and functionally transplantable. The inherent mobility of the M2 region promotes nucleosomal DNA-end unwrapping and persists when DNA ends are stabilized by linker histone H1 or opened by SUV420H1, indicating that this mobility is intrinsic rather than a passive consequence of DNA detachment. Chemical shift perturbation mapping and catalytic assays further show that SUV420H1 reads this H2A.Z-specific conformational landscape: the M2 region, together with the H2A.Z DS motif, supports variant-selective methyltransferase activity. These findings establish an axis of sequence-dynamics-accessibility-recognition along which local backbone fluctuations serve as physical determinants of epigenetic enzyme specificity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/731474v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@a50ceforg.highwire.dtl.DTLVardef@1f43af0org.highwire.dtl.DTLVardef@14969b8org.highwire.dtl.DTLVardef@bbbe0d_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Digital Twin Brain simulation and manipulation of a functional brain network underlying mental illness

Linking synaptic-level perturbations to distributed brain-network dynamics remains a central challenge for understanding and treating mental illness. Although recent whole-brain models can reproduce individual brain activity patterns, they largely function as descriptive simulators rather than mechanistic, intervention-capable systems. Here we present an intervention-capable digital twin of the human brain, integrating individual neuroanatomy and task-evoked dynamics within a neuronal-scale framework. Individualised digital twin brains recapitulate a participant-specific compact cortico-subcortical network phenotype that captures transdiagnostic psychopathology across population and clinical cohorts. In silico modulation of excitatory and inhibitory synaptic conductance produces bidirectional, heterogeneous network responses across individuals. Population-scale simulations stratify individuals and predict longitudinal symptom trajectories from DTB-derived response profiles. Independent pharmacological functional MRI data further validate the predicted baseline-dependent network responses in vivo. Together, these findings establish digital brain models as experimental platforms for mechanistic perturbation, behavioural prediction and stratification, providing a foundation for precision neuroscience and psychiatry.

neuroscience↗

bioRxiv2025

Cohesin Acetylation and ATPase Activity Control Cohesion and Loop Architecture through Distinct Mechanisms

Cohesin is a conserved protein complex that mediates sister chromatid cohesion, chromosome condensation, gene regulation, and DNA repair. These processes rely on cohesins ability to tether sister chromatids and form chromatin loops, which depend on cohesins ATPase activity and Eco1-mediated acetylation of two lysine residues (K112 and K113 in budding yeast) in its Smc3 subunit. How cohesins ATPase activity and acetylation integrate to control cohesin functions remains poorly understood. Here, we analyzed chromatin architecture in yeast mutants with altered cohesin acetylation and/or ATPase activity. We find that acetylation of either K112 or K113 is sufficient to produce a wild-type chromosome structure with loops positioned at cohesin-associated regions (CARs), whereas loss of acetylation at both residues abolishes positioned loops, indicating that acetylation at either lysine alone can maintain wild-type chromatin architecture. We further show that a cohesin acetylation mutant, despite being defective in sister-chromatid tethering and thus failing to establish cohesion, still forms wild-type-like loops, while cohesion-competent mutants lack positioned loops. These results suggest that the activities required for cohesion and loop formation are mechanistically separable, arguing against passive loop capture. Moreover, a mutant with reduced ATPase activity showed a loop profile similar to wild type, indicating that cohesin with lower ATPase activity can still form wild-type chromatin architecture. By contrast, hyper-ATPase mutants accumulate positioned loops, suggesting that increasing ATPase activity can enhance loop processivity. Together, our findings support a multilayered regulatory model in which acetylation fine-tunes ATPase output and cohesin functions to shape genome architecture.

genetics↗

bioRxiv2025

Brain Diffusion Transformer for Personalized Neuroscience and Psychiatry

Task-fMRI analyses typically focus on localized activation contrasts between stimuli, neglecting the brains dynamic hierarchy. We introduce Brain Diffusion Transformer (Brain-DiT), a deep generative model capturing recurrent processing underlying individualized neurocognitive state transitions via functional networks. Without prior assumptions, Brain-DiT identifies canonical cognitive regions in the brain and reveals replicable subgroups with distinct neural circuits in large cohorts, offering critical clinical insights overlooked by traditional methods: individuals exhibiting negative emotion bias, linked to language-related regions, had a 12-fold higher likelihood of major depression, and those with maladaptive inhibition strategies, associated with overactive medial frontal regions, showed a 9-fold increased risk of alcohol abuse. By bridging cognitive theory and psychiatric applications, Brain-DiT provides a unified analytical paradigm, paving the way for operational personalized medicine in psychiatry.

neuroscience↗

bioRxiv2024

Convergent representations and spatiotemporal dynamics of speech and language in brain and deep neural networks

Recent studies have explored the correspondence between single-modality DNN models (speech or text) and specific brain networks for speech and language. The key factors underlying these correlations and their spatiotemporal evolution within the brain language network remain unclear, particularly across different DNN modalities. To address these questions, we analyzed the representation similarity between self-supervised learning (SSL) models for speech (Wav2Vec2) and language (GPT-2), against neural responses to naturalistic speech captured via high-density electrocorticography. Our results indicated high prediction accuracy of both types of SSL models relative to neural activity before and after word onsets. It was the shared components between Wav2Vec2.0 and GPT-2 that explained the majority portion of the SSL-brain similarity. Furthermore, we observed distinct spatiotemporal dynamics: both models showed high encoding accuracy 40 milliseconds before word onset, especially in the mid-superior temporal gyrus (mid-STG), which can be explained by the shared contextual components in the SSL models; the Wav2Vec2.0 also peaked at 200 milliseconds after word onset around the posterior STG, which was mainly attributed to the acoustic-phonetic and static semantic information encoded in the SSL models. These results highlight how contextual and acoustic-phonetic cues encoded in DNNs align with spatiotemporal neural activity patterns, suggesting a significant overlap in how artificial and biological systems process linguistic information.

neuroscience↗

bioRxiv2024

Genetic-Dependent Brain Signatures of Resilience: Interactions among Childhood Abuse, Genetic Risks and Brain Function

Resilience to emotional disorders is critical for adolescent mental health, especially following childhood abuse. Yet, brain signatures of resilience remain undetermined due to the differential susceptibility of the brains emotion processing system to environmental stresses. Analyzing brains responses to angry faces in a longitudinally large-scale adolescent cohort (IMAGEN), we identified two functional networks related to the orbitofrontal and occipital regions as candidate brain signatures of resilience. In girls, but not boys, higher activation in the orbitofrontal-related network was associated with fewer emotional symptoms following childhood abuse, but only when the polygenic burden for depression was high. This finding defined a genetic-dependent brain (GDB) signature of resilience. Notably, this GDB signature predicted subsequent emotional disorders in late adolescence, extending into early adulthood and generalizable to another independent prospective cohort (ABCD). Our findings underscore the genetic modulation of resilience-brain connections, laying the foundation for enhancing adolescent mental health through resilience promotion.

neuroscience↗

bioRxiv2024

The molecular mechanism of temperature-dependent phase separation of Heat shock factor 1

Heat shock factor 1 (HSF1) is the critical orchestrator for a cell responding to heat shock, and its dysfunction is linked to cancers and neurodegenerative diseases. HSF1 undergoes phase separation upon heat shock, and its activity is regulated by various post-translational modifications (PTMs). Despite its importance, the molecular details underlying HSF1 phase separation, temperature sensing, and post-translational modifications (PTMs) regulation remain poorly understood. Here, we discovered that HSF1 exhibits temperature-dependent phase separation with a lower critical solution temperature (LCST) behavior due to entropy contribution from solvent molecules, providing a new conceptual mechanism accounting for HSF1 activation. We employed a synergistic approach combining coarse-grain simulation and nuclear magnetic resonance spectroscopy to reveal the residue-level molecular details of the interactions driving the phase separation of wild-type HSF1 and its distinct PTM patterns at various temperatures. The identified interaction sites were further validated with biochemistry assays and mapped interface accounts for HSF1 functions reported. Importantly, the amino acid substitution experiment reveals the molecular grammar for temperature-dependent HSF1 phase separation is species-specific and physiologically relevant. These findings delineate chemical code that integrates protein PTM patterns with accurate phase separation for body physiological temperature control in animals.

biochemistry↗

bioRxiv2024

Multivalent 28S rRNA Is the Organizer of the Nucleolus's Multi-layered Architecture

The nucleolus widely exists in all eukaryotic species. Throughout evolution, two types of nucleoli have emerged: bipartite, which has two-layered subcompartments, and tripartite, which features three nested sub-compartments: granular component (GC), dense fibrillar component (DFC), and fibrillar center (FC). FC and DFC form a core-shell architecture and are immersed by a large GC. However, factors that mediated the formation of the three-layered architecture remain largely unknown. Here, we discovered that rRNAs have specific localizations within the nucleolus, with 28S rRNA forming assemblies surrounding the DFC. Multivalent interactions of 28S rRNA drove the formation of the hollow shell structure of DFC, which mediated the development of a three-layered structure resembling nucleolar GC-DFC-FC. Moreover, in organisms with a tripartite nucleolus, 28S rRNA has evolved to acquire a higher degree of multivalency. Our data implies that the emergence of multivalency of 28S rRNA facilitates the transition of bipartite to tripartite nucleolus.

cell biology↗

bioRxiv2023

The roles of DDR2 and substrate stiffness on cancer cell transcriptome and proliferation

The interactions between cancer cells and the ECM regulate carcinogenesis. The collagen receptor kinase DDR2 is dysregulated in certain cancer cells, but its precise role in these malignancies remains unclear. In this study, we perform RNA-seq to determine how DDR2 and the biomechanical environment regulate cancer cell behaviors. We show that DDR2 knockdown in SH-SY5Y neuroblastoma cells inhibits proliferation and promotes senescence by regulating relevant genes. Increasing substrate stiffness reduces proliferation and promotes cell spreading but does not change senescence or transcriptome. Furthermore, DDR2 knockdown modulates cellular responses to substrate stiffness changes, unraveling a crosstalk between DDR2 and mechanosensing. These findings indicate DDR2 and ECM biomechanics regulate cancer cell behavior through distinct mechanisms, providing new mechanistic insights of cancer progression.

biochemistry↗

bioRxiv2023

A neural signature for the subjective experience of threat anticipation under uncertainty

Uncertainty about potential future threats and the associated anxious anticipation represents a key feature of anxiety. However, the neural systems that underlie the subjective experience of threat anticipation under uncertainty remain unclear. Combining a novel uncertain shock anticipation paradigm that allows precise modulation of the level of momentary anxious arousal during functional magnetic resonance imaging (fMRI) with multivariate predictive modeling, we trained a brain model that accurately predicted the intensity of subjective experience of anxious arousal on the population and individual level. In a series of analyses utilizing available fMRI datasets, we further demonstrate that the signature specifically predicted anxious anticipation and was not sensitive in predicting pain, general anticipation or unspecific arousal. The signature was functionally and spatially distinguishable from representations of subjective fear or negative affect. We developed a sensitive, generalizable, and specific neuromarker for subjective anxious arousal experienced during uncertain threat anticipation that can facilitate model development and clinical translation.

neuroscience↗

bioRxiv2023

Structural insights into Rad18 targeting by the SLF1 BRCT domains

Rad18 interacts with the SMC5/6 localization factor 1 (SLF1) to recruit the SMC5/6 complex to DNA damage sites for repair. The mechanism of the specific Rad18 recognition by SLF1 is unclear. Here, we present crystal structure of the tandem BRCT repeat (tBRCT) in SLF1 (SLF1tBRCT) bound with the interacting Rad18 peptide. Our structure and biochemical studies demonstrate that SLF1tBRCT interacts with two phosphoserines and adjacent residues in Rad18 for high affinity and specificity Rad18 recognition. We found that SLF1tBRCT utilizes mechanisms common among tBRCTs as well as unique ones for Rad18 binding, the latter include interactions with an -helical structure in Rad18 that has not been observed in other tBRCT-bound ligand proteins. Our work provides structural insights into Rad18 targeting by SLF1 and expands the understanding of BRCT-mediated complex assembly.

biochemistry↗

bioRxiv2022

A model for Scc2p Stimulation of Cohesin's ATPase and its Inhibition by Acetylation of Smc3p

The evolutionarily conserved cohesin complex mediates sister chromatid cohesion and facilitates mitotic chromosome condensation, DNA repair, and transcription regulation. These biological functions require cohesins two ATPases, formed by the Smc1p and Smc3p subunits. Cohesins ATPase activity is stimulated by the Scc2p auxiliary factor. This stimulation is inhibited by Eco1p acetylation of Smc3p at an interface with Scc2p. It was unclear how cohesins ATPase activity is stimulated by Scc2p, or how acetylation inhibits Scc2p, given that the acetylation site is distal to cohesins ATPase active sites. Here, we identify mutations in budding yeast that suppressed the in vivo defects caused by Smc3p acetyl-mimic and acetyl-defective mutations. We provide compelling evidence that Scc2p activation of cohesin ATPase depends upon an interface between Scc2p and a region of Smc1p proximal to cohesins Smc3p ATPase active site. Furthermore, substitutions at this interface increase or decrease ATPase activity to overcome ATPase modulation by acetyl-mimic and - null mutations. Using these observations and a cryo-EM structure, we propose a model for regulating cohesin ATPase activity. We suggest that Scc2p binding to Smc1p causes a shift in adjacent Smc1p residues and ATP, stimulating the Smc3p ATPase. This stimulatory shift is inhibited through acetylation of the distal Scc2p-Smc3 interface.

genetics↗

bioRxiv2022

Structural basis for the Rad6 activation by the Bre1 N-terminal domain

The mono-ubiquitination of the histone protein H2B (H2Bub1) is a highly conserved histone post-translational modification that plays critical roles in many fundamental processes. In yeast, this modification is catalyzed by the conserved Bre1-Rad6 complex. Bre1 contains a unique N-terminal Rad6 binding domain (RBD), how it interacts with Rad6 and contributes to the H2Bub1 catalysis is unclear. Here, we present crystal structure of the Bre1 RBD-Rad6 complex and structure-guided functional studies. Our structure provides a detailed picture of the interaction between the dimeric Bre1 RBD and a single Rad6 molecule. We further found that the interaction stimulates Rad6s enzymatic activity by allosterically increasing its active site accessibility and likely contribute to the H2Bub1 catalysis through additional mechanisms. In line with these important functions, we found that the interaction is crucial for multiple H2Bub1-regulated processes. Our study provides molecular insights into the H2Bub1 catalysis.

biochemistry↗

bioRxiv2022

Manipulating Oxalate Decarboxylase Provides the Basis of Antilithic Therapy by Acting on the Gut Microbiota

A high concentration of oxalate is associated with an increased risk of kidney calcium oxalate (CaOx) stones, and the degradation of exogenous oxalate mainly depends on oxalate-degrading enzymes from the intestinal microbiome. We found that Zinc Gluconate supplement to patients with CaOx kidney stones could significantly improve the abundance of oxalate metabolizing bacteria in human body through clinical experiments on the premise of simultaneous antibiotic treatment and the imbalance of Lactobacillus and OxDC was involved in CaOx kidney stones through clinical sample analysis. Then, we identified that Zn2+ could be used as an external factor to improve the activity of OxDC and protect Lactobacillus, achieved the preventive effect on rats with stones aggravated by antibiotics. Finally, by analyzing the three-dimensional structure of OxDC and some in vitro experiments, we propose a hypothesis Zn2+ increases the metabolism of oxalate in humans through its positive effects on Lactobacillus and OxDC to reduce CaOx kidney stone symptoms in rats. IMPORTANCEUrinary stone disease is one of the most common urological disorders, and 70%-80% of urinary stones are calcium oxalate (CaOx) stones. We found the structural basis and metabolic mechanism by which oxalate decarboxylase metabolizes oxalate were elucidated, and Zn2+ was illustrated to have therapeutic effects on CaOx stones by improving the tolerance of Lactobacillus to antibiotics. According to that, proper Zn2+ levels in the diet, the consumption of more probiotic food and avoidance of the antibiotic overuse might be desirable measures for the prevention and treatment of kidney stones. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/512337v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@d3df85org.highwire.dtl.DTLVardef@1f7b3f5org.highwire.dtl.DTLVardef@147d861org.highwire.dtl.DTLVardef@1cf046e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Genome-wide analyses of PAM-relaxed Cas9 genome editors reveal substantial off-target effects by ABE8e in rice

PAM-relaxed Cas9 nucleases, cytosine base editors and adenine base editors are promising tools for precise genome editing in plants. However, their genome-wide off-target effects are largely undetermined. Here, we conduct whole-genome sequencing (WGS) analyses of transgenic plants edited by xCas9, Cas9-NGv1, Cas9-NG, SpRY, nCas9-NG-PmCDA1, nSpRY-PmCDA1 and nSpRY-ABE8e in rice. Our results reveal different guide RNA (gRNA)-dependent off-target effects with different editors. De novo generated new gRNAs by SpRY editors lead to additional but not substantial off-target mutations. Strikingly, ABE8e results in ~500 genome-wide A-to-G off-target mutations at TA motif sites per transgenic plant. The preference of the TA motif by ABE8e is also observed at the target sites. Finally, we investigate the timeline and mechanism of somaclonal variation due to tissue culture, which chiefly contributes to the background mutations. This study provides a comprehensive understanding on the scales and mechanisms of off-target and background mutations during PAM-relaxed genome editing in plants.

genetics↗

bioRxiv2021

A novel analytical decoder of BOLD signals for dissociating latent neurobehavioral processes

How to retrieve latent neurobehavioral processes from complex neurobiological signals is an important yet unresolved challenge. Here, we develop a novel approach, orthogonal-Decoding multi-Cognitive Processes (DeCoP), to reveal underlying latent neurobehavioral processing and show that its performance is superior to traditional non-orthogonal decoding in terms of both false inference and robustness. Processing value and salience information are two fundamental but mutually confounded pathways of reward reinforcement essential for decision making. During reward/punishment anticipation, we applied DeCoP to decode brain-wide responses into spatially overlapping, yet functionally independent, evaluation and readiness processes, which are modulated differentially by meso-limbic vs nigro-striatal dopamine systems. Using DeCoP, we further demonstrated that most brain regions only encoded abstract information but not the exact input, except for dACC and insula. Furthermore, our novel analytical principle could be applied generally to decode multiple latent neurobehavioral processes and thus advance both the design and hypothesis testing for cognitive tasks.

neuroscience↗

bioRxiv2021

Sift-PULs: A public repository for specific functional polysaccharide utilization loci

BackgroundPolysaccharide utilization loci (PULs) were bacterial gene clusters encoding genes responsible for polysaccharide utilization process. PUL studies are blooming in recent years but the biochemical characterization speed is relative slow. There is a growing demand for PUL database with function annotations. ResultsUsing signature genes corresponding for specific polysaccharide, 10422 PULs specific for 6 polysaccharides (agar, alginate, pectin, carrageenan, chitin and {beta}-manan) from various bacterial phyla were predicted. Then online website of specific functional polysaccharide utilization loci (Sift-PULs) was constructed. Sift-PULs provides a repository where users could browse, search and download interested PULs without registration. ConclusionsThe key advantage of Sift-PULs is to assign a function annotation of each PUL, which is not available in existing PUL databases. PULs functional annotation lays a foundation for studying novel enzymes, new pathways, PUL evolution or bioengineering. The website is available on https://sift-puls.org

bioinformatics↗