Biology subjects

Yan, Z.

Publications and source records attributed to Yan, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Structure-guided reinterpretation of a disease-associated CWH43 residue-533 truncation identifies internal disruption of a conserved C-terminal module in idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is a chronic neurological disorder characterized by ventricular enlargement together with gait impairment, cognitive decline, and urinary dysfunction. Disease-associated CWH43 variants have emerged as genetic clues in iNPH, but the molecular consequences of truncating variants remain poorly defined. Here, we used structure-guided analysis to reinterpret the disease-associated human CWH43 variant c.1596del, annotated as p.Leu533Ter and referred to here as the residue-533 truncation. AlphaFold-based modeling of the full-length 699-amino-acid protein supported a conserved C-terminal D3 module spanning residues 407-699. Within this framework, the residue-533 truncation is best interpreted as an internal interruption of D3 rather than deletion of a poorly constrained terminal tail. Pocket analysis identified a dominant candidate surface site within D3 containing 18 pocket-lining residues, 55.6% of which (10/18) are removed by truncation. Independent cavity mapping further showed that the affected region is better understood as a broader cavity-bearing architecture rather than a single local pocket. Cross-boundary contact analysis, multi-model reproducibility, and representative local geometry supported structural coupling between retained and deleted D3 segments, indicating that truncation is predicted to cause retained-side decoupling in addition to direct residue loss. Together, these findings support a model in which the disease-associated residue-533 truncation disrupts a structurally integrated C-terminal module and its associated cavity-bearing architecture. This framework refines interpretation of CWH43-associated iNPH variants and provides a mechanistic bridge between human genetic association and architecture-level loss of function.

genetics↗

bioRxiv2026

SIRPA suppresses integrin-dependent virus endocytosis

New World arenaviruses (NWAs) that cause viral hemorrhagic fever, such as Junin virus, have few therapeutic options. Entry of these viruses into cells is mediated by binding to cell surface receptors, followed by endocytosis and trafficking to a low pH compartment. We showed previously that Signal Regulatory Protein Alpha (SIRPA), a critical cell surface receptor that inhibits macrophage phagocytic activity, decreases internalization by NWAs as well as other pathogenic RNA viruses that traffic to low pH compartments. Here we demonstrate that proteins involved in the SIRPA/integrin signaling axis, including Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), src family kinases (SFKs), particularly FYN, focal adhesion kinase (FAK), and alpha-integrin play a role in viral endocytosis and that SIRPA inhibits virus entry through blocking this pathway. In addition to defining a role for integrins in viral entry, these studies also provide additional insight into SIRPAs interference in processes dependent on integrin signaling, including phagocytosis. Moreover, using drugs that block the integrin signaling pathway in vitro and in vivo, we show that there are additional steps that may be targeted therapeutically for inhibiting infection by RNA viruses that traffic to acidic compartments.

cell biology↗

bioRxiv2026

Elevating levels of neuronal MCU in the hippocampus enhances mitochondrial calcium uptake and respiratory efficiency proportional to demand

Mitochondrial calcium signaling integrates energy needs with energy production, amplifying or suppressing mitochondrial respiration in response to activity demand. Neuronal activity is tightly ATPcoupled to increases in mitochondrial calcium uptake, which stimulate the tricarboxylic acid cycle (TCA) and activate calcium-dependent enzymes important for ATP production via oxidative phosphorylation. The mitochondrial calcium uniporter (MCU) is the predominant source of matrix calcium and is differentially expressed across neuronal cell types, suggesting cell-type-specific differences in the coupling of activity-driven calcium levels and mitochondrial respiration. Here, we investigated whether elevating MCU expression enhances mitochondrial calcium uptake and oxidative phosphorylation in the hippocampus. We report that hippocampal mitochondria overexpressing MCU take up calcium at a faster rate without increased sensitivity to calcium overload. By modeling in vivo supply and demand, we found that hippocampal mitochondria overexpressing MCU are more efficient than control mitochondria at responding to increased bioenergetic demand. These findings reveal a role for MCU in modulating mitochondrial calcium uptake and boosting mitochondrial respiration under increasing demand, which contributes to our understanding of how specific cell types may adapt to different bioenergetic demands.

neuroscience↗

bioRxiv2026

In vivo-compatible spatial multi-omics via hydrogen peroxide-independent APEX2 labeling

Proximity labeling (PL) technologies like APEX2 have transformed spatial multi-omics in live cells, but their long-standing dependence on hydrogen peroxide (H2O2) disrupts redox signaling and prevents use in live animals. Here we introduce H2O2-independent APEX2 (Hi-APEX), which uses a clickable tetrazine-phenol probe, requiring no enzyme engineering. We show that APEX2 directly catalyzes TP radical formation without H2O2 via a mechanism requiring the probes tetrazine group and a key histidine residue. We benchmarked Hi-APEX-based spatial multi-omics by mapping the mitochondrial matrix and dynamic secretomes. Hi-APEX significantly outperforms traditional APEX in capturing redox-sensitive processes such as stress response and ferroptosis, enabling discovering authentic stress granule components and protein interaction networks for mitochondria-localized GPx4. One mGPx4 interactor TRMT61B--known to regulate mitochondrial m{superscript 1}A modifications--promotes ferroptosis. Crucially, Hi-APEX achieves full in vivo compatibility, enabling direct PL in tumor xenografts and hippocampal neurons, thereby expanding PL-based spatial multi-omics from cellular systems to living organisms.

biochemistry↗

bioRxiv2026

Sampling Mismatch and Correction for Ptychographic Single-Particle Analysis

Ptychographic single-particle analysis (SPA) is a promising technique for high-resolution biological imaging but is still limited by sub-nanometer resolution. In this study, we identified and investigated a critical issue termed sampling mismatch in ptychography that is caused by inaccuracies in the scanning step size and the pixel size of convergent beam electron diffraction (CBED) images. This mismatch induces pixel-size deviations in the reconstructed micrographs and modulates information transfer through a mismatch-induced modulation function (MIMF), which is characterized by phase reversals at specific spatial frequencies of the micrographs. These phase reversals, which vary with the defocus, cause destructive interference when merging micrographs, fundamentally limiting the resolution of SPA. We proposed a correction strategy and demonstrated, on the T. Acidophilum 20S proteasome and apoferritin datasets, that correcting sampling parameters eliminates signal distortions and improves resolution for [~]1.5 [A]. These findings underscore the necessity for the precise control and calibration of the scanning system to achieve high-resolution ptychographic SPA.

biophysics↗

bioRxiv2026

Discrete Transcriptional States Define Biphasic Immune Response and Dynamic CMS Transitions in Colorectal Cancer

BackgroundSequential alterations in APC, KRAS, TP53, and SMAD4 have been proposed as a framework for colorectal cancer progression. Human colorectal cancer datasets have not revealed the biological transitions associated with these mutations. When examining a cohort of TCGA-colorectal tumors grouped as AK (APC/KRAS), AKP (APC/KRAS/TP53), and AKPS (APC/KRAS/TP53/SMAD4), we observed no significant differences in immune-cell composition, four previously defined Consensus Molecular Subtypes (CMS1/2/3/4), or transcriptomic clustering between these genomic groups. Therefore, these canonical alterations do not sufficiently characterize the known properties of metastatic progression in human colorectal cancer. MethodsTo overcome these limitations, we developed a genetically defined, organoid-based, orthotopic mouse model whereby mouse colon organoids modeling sequential APC, KRAS, TP53, and SMAD4 alterations were orthotopically injected into the colon. This was followed by RNA-sequence processing, normalization with DESeq2, differential expression, pathway enrichment, and immune/stromal inference. Gene co-expression modules were identified from variance-stabilized mouse expression data, mapped to 1:1 human orthologs, and summarized as eigengenes. A multinomial logistic regression model trained on mouse eigengenes was applied to TCGA-COAD human tumors to assign them to mouse-informed transcriptomic states (AK-like, AKP-like, AKPS-like), which were then used for downstream visualization and comparative analyses. ResultsWhole-transcriptome analysis revealed discrete transcriptional states and immune-cell differences between the organoid AK/AKP/AKPS groups. Early TP53 loss led to strong activation of immune pathways, accompanied by increased infiltration of NK and T cells. As tumors progressed with SMAD4 loss and metastasis, this immune activity collapsed, giving rise to broad immune suppression. CMS classifications also shifted, with AK tumors resembling epithelial CMS2, AKP tumors displaying immune-rich CMS1 features, and AKPS and metastatic lesions adopting mesenchymal CMS4 characteristics. We then applied a progression-based transcriptomic classifier to 460 human colorectal tumors. This reclassification revealed conserved immune remodeling, CMS transitions, pathway-level differences, and significant differences in patient survival. ConclusionWe show that organoid-derived progression profiles reveal hidden evolutionary structure in human colorectal cancer and provide a transcriptional framework for interpreting metastatic potential and clinical outcomes.

cancer biology↗

bioRxiv2026

Gliomas preferentially develop within the action-mode network

Gliomas tend to arise in specific brain regions and may integrate into functional circuits, suggesting they could be regulated by brain activity. However, it remains unclear whether glioma growth is related to system-level brain networks. Analyzing neuroimaging data from three datasets including 1,310 patients with cerebral gliomas, we identified and replicated a functionally connected glioma network, which overlaps with the action-mode network (AMN), somatomotor network (SMN), and action-related subcortical regions. Resting-state functional connectivity (RSFC) of the AMN successfully predicted the location of glioma occurrence in two independent datasets with complex tumor distributions. Remarkably, no patient had a glioma entirely outside the AMN, and over 89% of patients exhibited gliomas with at least 50% overlap with the network. Moreover, the spatial overlap between glioma location and the AMN demonstrated significant prognostic value in survival analyses, with higher AMN-tumor overlap associated with poorer overall survival. Notably, the acetylcholine transporter, a key player in glioma pathogenesis that drives transcriptional reprogramming, showed an expression pattern overlapping with the AMN. Meta-analytic annotations further linked the glioma network to processes of action initiation, execution, and feedback. These findings indicate that gliomas preferentially arise in circuits involved in action and highlight the central role of the AMN in glioma pathophysiology and growth.

neuroscience↗

bioRxiv2025

PROX1 loss in adult mouse Schlemm's canal causes permanent ocular hypertension

Glaucoma is associated with ocular hypertension and lowering intraocular pressure is a key objective of glaucoma therapies. Recent studies have established a role for the Schlemms canal endothelium in this pressure increase and have shown it to have a unique, lymphatic-like, hybrid phenotype. However, the role of these lymphatic phenotypes in the adult canal remains uncertain. Long-term functional studies have been limited by systemic importance of lymphatic genes and lack of Schlemms canal-specific animal models. Here, we designed and validated a strategy using 4OH-tamoxifen-loaded nanocarriers to generate targeted, Schlemms canal specific knockout mice lacking lymphatic phenotypes. Using this system, we selectively deleted Prox1, the master transcription factor governing lymphatic fate. Within four weeks, intraocular pressure significantly increased, and ocular hypertension was maintained for at least 24 weeks. Unlike lymphatic vessels, which degenerate following Prox1 deletion, Schlemms canal reverted to a less functional vein-like phenotype with no change in size or morphology. These results highlight the utility of nanocarriers for tissue-specific genetic recombination and demonstrate that changes in lymphatic phenotypes alter intraocular pressure, providing new targets for glaucoma therapy. Moreover, as we found that PROX1 was downregulated with age in human Schlemms canal, these canal-specific conditional Prox1 knockout mice are a valuable new adult-onset model of ocular hypertension that captures key features of age-related human disease.

physiology↗

bioRxiv2025

Dissecting mammalian cortical circuit development at single-cell resolution using inducible barcoded rabies virus

Highly organized circuits of connected neurons enable diverse brain functions. Improper development of these circuits is associated with neurodevelopmental disorders, and understanding how circuits are formed is crucial for unraveling the mechanisms of these diseases. We currently have an incomplete picture of how specific brain circuits develop and how they are affected in disease, because we lack methods to study them at scale and with single-cell resolution. Monosynaptic rabies tracing is the gold standard method to study circuit architecture. However, it suffers from cellular toxicity, low throughput, lack of control over the timing of labeling, and the inability to access the molecular profiles of individual neurons. To address these issues, we developed an inducible barcoded rabies virus (ibRV) to enable temporal-controlled labeling of synaptic circuits followed by high-throughput single-cell genomics readout. ibRV allows for dissecting neuronal circuit changes over time at single-cell and spatial resolution. We applied ibRV to study the development of specific mouse cortical circuits during late prenatal and postnatal life using single-cell genomics and unbiased spatial transcriptomics as readouts. We characterized and quantified developmental connectivity patterns and molecular cascades that underlie their formation. Additionally, we constructed functional in silico circuit models that enable interrogation of circuit function and dysfunction at specific developmental stages. Our study provides novel tools for circuit analysis and can provide new insights into the mechanisms of mammalian brain development.

neuroscience↗

bioRxiv2025

PERM1 Gene Delivery via AAV Prevents Heart Failure in a Mouse Model of Pressure Overload

Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of mortality worldwide. A hallmark of HFrEF is impaired cardiomyocyte contractility accompanied by disrupted mitochondrial bioenergetics; however, no current therapy targets both pathologies simultaneously. PERM1, a striated muscle-specific regulator of mitochondrial bioenergetics, is downregulated in HFrEF patients. We recently demonstrated that overexpression of PERM1 via adeno-associated virus 9 (AAV9-PERM1) enhances both cardiac contractility and mitochondrial biogenesis in C57BL/6 mice. In this study, we evaluated the therapeutic potential of AAV9-PERM1 in a pressure overload-induced mouse model of HFrEF. C57BL/6 mice were treated with either AAV9-PERM1 or control AAV9-GFP (1x1012 GC/mouse), followed by transverse aortic constriction (TAC) surgery. At 4 weeks post-TAC, control mice receiving AAV-GFP exhibited reduced left ventricular ejection fraction (LVEF), whereas AAV-PERM1 preserved LVEF at baseline levels. This cardioprotective effect was sustained through 8 weeks. Notably, AAV9-PERM1 completely abrogated TAC-induced cardiac hypertrophy and fibrosis. Mitochondrial analysis revealed that AAV9-PERM1 preserved mitochondrial DNA copy number and TFAM protein levels, both of which were reduced by TAC in control hearts. AAV9-PERM1 also improved mitochondrial respiration using pyruvate and octanoylcarnitine as substrates and prevented TAC-induced impairments in oxidative capacity. While PGC-1 expression remained unchanged in control TAC hearts, it was modestly yet significantly upregulated by AAV9-PERM1 in both sham and TAC groups. In addition, AAV9-PERM1 suppressed TAC-induced increases in O-GlcNAcylation, a stress-related posttranslational modification of proteins. Co-immunoprecipitation further revealed interactions of PERM1 with creatine kinase and troponin C, key proteins in ATP transduction and contractility, suggesting a functional coupling between mitochondrial energetics and contractility. In conclusion, AAV-PERM1 gene therapy effectively preserves cardiac function under pressure overload by maintaining mitochondrial biogenesis, respiration capacity and contractility. This study further suggests AAV-PERM1 as a promising therapeutic strategy for HFrEF.

physiology↗

bioRxiv2025

Ampk alpha2 T172 Activation Dictates Exercise Performance and Energy Transduction in Skeletal Muscle

AMPK (5'-AMP-activated protein kinase) is an energetic sensor for metabolic regulation and integration. Here, we employed CRISPR/Cas9 to generate non-activatable Ampk knock-in (KI) mice with mutation of threonine 172 phosphorylation site to alanine, circumventing the limitations of previous genetic interventions that disrupt the protein stoichiometry. KI mice of Ampk2, but not Ampk1, demonstrated phenotypic changes with increased fat-to-lean mass, impaired endurance exercise capacity, and diminished mitochondrial maximal respiration and conductance in skeletal muscle. Integrated temporal multi-omic analysis (proteomics/phosphoproteomics/metabolomics) in skeletal muscle at rest and during exercise establishes a pleiotropic yet imperative role of Ampk2 T172 activation for glycolytic and oxidative metabolism, mitochondrial respiration, and contractile function. Importantly, there is a significant overlap of skeletal muscle proteomic changes in Ampk2 T172A KI mice with that of type 2 diabetic patients. Our findings suggest that Ampk2 T172 activation is critical for exercise performance and energy transduction in skeletal muscle and may serve as a therapeutic target for type 2 diabetes.

molecular biology↗

bioRxiv2025

Machine-learning-based automated Schlemms canal volumetric segmentation for optical coherence tomography

Volumetric segmentation of Schlemms Canal (SC) in optical coherence tomography (OCT) is time-consuming, creating a barrier to experiments studying glaucoma and the anatomy of the trabecular outflow pathways in vivo. To this end, we developed an automated segmentation tool, Schlemms Canal-Localization and Semantic Segmentation (SC-LSS), for the volumetric segmentation of SC in in vivo mice eyes from visible-light OCT (vis-OCT). SC-LSS first localizes the boundaries of SC and subsequently determines the boundaries of SC within the localized region. We used 324 B-scans from 16 mouse eyes for training, validation, and testing the model, and 203 additional B-scans from 16 mouse eyes to evaluate the models accuracy. We found that the Dice coefficient between segmentations generated by SC-LSS and manual expert graders was 0.70 {+/-} 0.20 and that the Dice coefficient between two expert graders was 0.73 {+/-} 0.18 (p = 0.10). Furthermore, SC-LSS captured decreases in SC size with increasing intraocular pressure, yielding a 51.5% decrease in SC size at 20 mmHg compared to 5 mmHg. SC-LSS also identified a 20.1% increase in SC size following the administration of pilocarpine. We anticipate that SC-LSS will accelerate studies on factors regulating the trabecular outflow pathways and their role in glaucoma development and management.

bioengineering↗

bioRxiv2025

Chronic Cervical Midline Contusion in Rats Disrupts Aerobic, Muscular, and Cardiovascular Function

Cardiovascular dysfunction significantly contributes to morbidity and mortality following cervical spinal cord injury (SCI). Unfortunately, only a limited number of preclinical models have been developed for investigating cardiovascular dysfunction following cervical SCI. Furthermore, the broader consequences of cervical SCI on aerobic capacity and muscle endurance during physiological stress testing also remains understudied preclinically. Therefore, in this study we assessed potential deficits across multiple physiological systems in a rat model of cervical SCI using a battery of stress tests. Female Sprague-Dawley rats (n = 20) received either a C8 midline contusion (cSCI) or laminectomy alone as a control (LAM). Exercise stress testing was conducted to evaluate cardiorespiratory fitness and recovery using a metabolic treadmill, or forelimb fitness using the isometric pull task. Orthostatic stress testing and pharmacological stress testing were also performed to more directly challenge the cardiovascular system. Our findings demonstrate a decline in aerobic fitness in cSCI rats, as evidenced by dysregulated excess post-exercise oxygen consumption. cSCI rats also exhibited impaired muscle endurance compared to LAM. During orthostatic stress testing, 70% of cSCI rats experienced an approximately 25 mmHg decrease in systolic blood pressure and 20 mmHg decrease in diastolic blood pressure, in addition to modest but significant decreases in heart rate, myocardial contractility index, stroke volume index, and cardiac output index. During dobutamine infusion, cardiac output index and stroke volume index were significantly reduced following cSCI compared to LAM. Overall, these stress testing results suggest that preclinical cervical SCI in rats can lead to, and therefore model, clinically relevant impairments in cardiopulmonary exercise performance, muscle endurance, and cardiovascular function.

physiology↗

bioRxiv2025

BioinAI: a general bioinformatic framework for multi-level transcriptomic data analysis using multiple semi-agents

Clinical and biological insights from large-scale transcriptomic data are often limited by technical variability and analytical complexity. Here, we introduce BioinAI, a general bioinformatic framework designed for multi-level transcriptomic data analysis. As part of the BioinAI framework, two algorithms named DeepAdvancer and stNiche were developed to improve data integration and analytical efficiency. DeepAdvancer leverages a class-aware adversarial autoencoder to reconstruct gene-expression profiles from 49,738 samples across 131 skin conditions. These profiles revealed a conserved inflammatory axis and a transcriptomic continuum which link diverse diseases through shared immune responses and structural programs. stNiche leverages spatial graph networks and symmetry-aware matching to identify functional cellular niches and reveals microstructural alterations across development, homeostasis, and disease. For instance, it identified a fibroblast-immune niche surrounding hair follicles in healthy skin, which disappears in pathological states. In addition, BioinAI provides a user-friendly online analysis platform powered by multiple semi-agents (www.bioinai.com), significantly facilitating the extraction of biological insights to advance scientific research.

bioinformatics↗

bioRxiv2025

Modeling Post-Gastrula Development via Bidirectional Pluripotent Stem Cells

The absence of stem cells capable of efficiently generating both trophoblast and epiblast lineages has hindered precise recapitulation of embryonic development. Through high-content chemical screening, we established an AL medium to generate mouse and human bidirectional pluripotent stem cells (BPSCs) characterized by concurrent OCT4/CDX2 expression. Mouse BPSCs demonstrated high plastic differentiation into trophoblast, epiblast and primitive endoderm lineages in vitro within 48 hours without exogenous induction factors and efficiently contributed to the embryo and extraembryonic tissues in vivo. Mechanistically, hyperactivation of the Wnt signaling pathway breaks the early lineage differentiation barrier by initiating a Lef1-dependent bypass. Remarkably, BPSCs can efficiently generated E8.5 embryoids that completed gastrulation and displayed advanced features such as brain development, a closed neural tube, a beating heart, somite formation, and primordial germ cells. These findings highlight BPSCs as a powerful tool for investigating early lineage specification and post-gastrulation embryonic development, with potential applications across multiple species.

developmental biology↗

bioRxiv2025

Proof-of-Concept in a Murine Model of Treatment of Thrombotic Thrombocytopenic Purpura Using Engineered Red Blood Cells

Thrombotic Thrombocytopenic Purpura (TTP) is caused by congenital or acquired deficiency of ADAMTS13, a metalloproteinase that cleaves von Willebrand Factor (vWF) multimers. Current treatments--plasma exchange and immunosuppression--are costly and associated with significant morbidity therefore, alternative strategies are needed. We developed the kitJak2 platform for producing genetically engineered lab-grown red blood cells (lgRBCs) as drug delivery vectors. We hypothesized that membrane-bound ADAMTS13 displayed on lgRBCs could provide a durable treatment for TTP. To test this, we engineered erythroid cells expressing both wild-type and mutant variants MDTCS fragments of ADAMTS13, conferring resistance to autoantibodies. Flow cytometry and FRET-based assays confirmed robust membrane expression and enzymatic activity. Importantly, mutant MDTCS variants retained catalytic activity in the presence of plasma from TTP patients, whereas wild-type variants were inhibited. For in vivo evaluation, we generated transgenic mice expressing MDTCS ADAMTS13 on their RBC membranes. These mice exhibited normal RBC half-lives and stable, catalytically active ADAMTS13 expression. Using a murine model of TTP--where ADAMTS13 knockout mice challenged with recombinant human vWF (rhvWF) develop thrombocytopenia and schistocytes--we demonstrated that transfusion of ADAMTS13-expressing RBCs significantly mitigated disease, preventing platelet loss and schistocyte formation. This confirms that membrane-bound MDTCS ADAMTS13 cleaves circulating rhvWF under physiological flow conditions in vivo. Finally, employing our KitJak2 platform, we generated human enucleated lgRBCs expressing high levels of catalytically active ADAMTS13. This novel work establishes proof-of-concept that membrane-anchored ADAMTS13-expressing lab- grown RBCs may offer a feasible and effective therapeutic approach for both congenital and acquired TTP.

cell biology↗

bioRxiv2025

Secondary structure transitions and dual PIP2 binding define cardiac KCNQ1-KCNE1 channel gating

The KCNQ1+KCNE1 potassium channel complex forms the slow delayed rectifier current (IKs) critical for cardiac repolarization. Loss-of-function variants in KCNQ1 and KCNE1 cause long QT syndrome types 1 and 5 (LQT1/LQT5), accounting for over one-third of clinical LQTS cases. Despite prior structural work on KCNQ1 and KCNQ1+KCNE3, the structural basis of KCNQ1+KCNE1 remains unresolved. Using cryo-EM and electrophysiology, we determined high-resolution (2.5-3.4 [A]) structures of human KCNQ1+KCNE1 in both closed and open states. KCNE1 occupies a pivotal position at the interface of three KCNQ1 subunits, inducing seven "helix-to-loop" transitions in KCNQ1 transmembrane segments. These structural rearrangements: 1) stabilize the closed pore and the conformation of the intermediate voltage-sensing domain, thereby determining channel gating, ion permeation, and single channel conductance; 2) enable a dual-PIP2 modulation mechanism, where one PIP2 occupies the canonical site, while the second PIP2 bridges the S4-S5 linker, KCNE1, and the adjacent S6, stabilizing channel opening; 3) create a fenestration capable of binding compounds specific for KCNQ1+KCNE1 (e.g., AC-1). Together, these findings reveal a previously unrecognized large-scale secondary structural transition during ion channel gating that fine-tunes IKs function and provides a foundation for targeted LQTS therapy development.

biophysics↗

bioRxiv2025

Cognitive and Synaptic Impairment Induced by Deficiency of Autism Risk Gene Smarcc2 and its Rescue by Histone Deacetylase Inhibition

SMARCC2, which encodes BAF170, a core subunit of chromatin remodeling BAF complex, is one of the top-ranking risk genes for autism spectrum disorder (ASD). However, the mechanisms linking SMARCC2 haploinsufficiency to ASD remain poorly understood. Genome-wide RNA-seq analysis revealed that SMARCC2 was significantly diminished in iPSC-derived neurons from idiopathic ASD patients. ChIP-seq of SMARCC2 demonstrated its binding to many other ASD risk genes involved in transcriptional regulation. Smarcc2 deficiency in prefrontal cortex (PFC) of adolescent mice led to impaired working memory, with largely intact social and anxiety-like behaviors. Significant downregulation of genes enriched in synaptic transmission were found in PFC of Smarcc2-deficient mice by RNA-seq and qPCR profiling. In parallel, electrophysiological recordings uncovered the significant impairment of GABAergic and glutamatergic synaptic currents in Smarcc2-deficient PFC pyramidal neurons. Smarcc2 bound to HDAC2, and Smarcc2 deficiency led to the reduced global histone acetylation and H3K9ac enrichment at synaptic gene Slc1a3 (EAAT1), Slc6a1 (GAT1), and Slc32a1 (VGAT) promoters. Treatment of Smarcc2-deficient mice with romidepsin, a class I HDAC inhibitor, restored histone acetylation, working memory and some synaptic gene expression. These findings highlight the critical role of Smarcc2 in regulating cognitive and synaptic function, suggesting that targeting HDAC could alleviate deficits in Smarcc2-associated neurodevelopmental disorders.

neuroscience↗