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Biology subjects

Park, H. J.

Publications and source records attributed to Park, H. J..

At least 19 recordsLinked to original sources

Prediction transfer does not imply reliability transfer in single-cell foundation models

Single-cell foundation models are increasingly transferred across tissues, diseases, perturbation screens, and experimental platforms. Although substantial effort has focused on prediction transfer, it remains unclear whether a model's assessment of its own reliability transfers similarly across biological contexts. Here we define reliability transfer as the ability to transfer an accurate assessment of when model predictions are likely to be correct or incorrect and investigate its behavior across ten perturbation-prediction systems spanning multiple datasets, models, and evaluation settings. We find that reliability transfer varies substantially across source-target pairs and cannot be inferred from predictive performance alone, indicating that prediction transfer and reliability transfer constitute distinct forms of generalization. Analyses of biological annotations, network connectivity, target exposure, and contextual factors reveal that prediction reliability is associated with both shared and context-dependent signals, with their relative importance differing across systems. To characterize this variability, we introduce reliability-attribution fingerprints, context-level signatures derived from strictly cross-fitted SHAP explanations that summarize how reliability estimators combine biological and contextual information when assigning confidence. Across systems, contexts with similar attribution-magnitude fingerprints tended to transfer reliability more successfully, and fingerprint similarity identified transfer sources achieving higher reliability-transfer performance within the observed candidate set. However, these relationships weakened under stricter cross-family transfer settings, indicating that transferable reliability structure remains partly dependent on shared contextual information. Finally, transferred reliability estimators produced different perturbation rankings despite identical perturbation predictions, illustrating a practical consequence of reliability transfer for downstream prioritization. Together, these results establish reliability transfer as a distinct aspect of foundation-model generalization and introduce reliability-attribution fingerprints as a framework for characterizing transferable reliability structure across biological contexts.

bioinformatics↗

ADSS1 is a suppressed metabolic control node in dystrophic skeletal muscle

Duchenne muscular dystrophy is initiated by dystrophin loss but is accompanied by profound metabolic remodelling. Here, we identify suppression of the muscle-enriched adenylosuccinate synthase, ADSS1, and the purine nucleotide cycle in mdx muscle. Integrated multi-omic profiling revealed a compensated purine-stress state in which nucleotide salvage and quality control were increased to preserve adenine nucleotide abundance and buffer consequential toxic/disruptive deoxy-/nucleotide production. Purine metabolism was the highest-impact joint pathway with metabolite and transcript hits in mdx muscle, and its maintenance program was directionally conserved in human ADSS1 myopathy. Interventions positioned around ADSS1 separated the outputs of this node. Ribose and dimethyl fumarate remodelled upstream or downstream stress programs, whereas only adenylosuccinic acid bypassed ADSS1 to expand the adenine nucleotide pool and remodel CoA/acetyl-CoA metabolism. All three interventions suppressed pro-adipogenic transcription without broadly correcting the lipidome. These findings identify ADSS1 as a regulated metabolic control node that couples purine retention to inflammatory and adipogenic remodelling in dystrophic muscle.

molecular biology↗

eQTM (expression quantitative trait methylation) Atlas: a comprehensive resource of over 11 million DNA methylation-gene expression associations through across 11 tissues and 4 diseases

MotivationEpigenome-wide association studies (EWAS) have identified numerous DNA methylation (DNAm) CpG sites associated with complex traits and diseases, but interpretation of those CpG sites remains challenging because in EWAS, CpGs are mostly linked to nearby genes based only on genomic proximity. Expression quantitative trait methylation (eQTM) analyses connect DNAm CpGs with statistically associated gene expression levels. However, a comprehensive, searchable resource integrating eQTMs across diverse tissues and disease contexts has been lacking. ResultsWe developed the eQTM Atlas, a web-based resource that manually curates more than 11 million DNAm-gene expression associations from eight cohorts, covering 11 tissue types, four broad disease contexts, 173,886 unique CpG probes and 20,231 unique genes. The Atlas supports gene- or CpG-searches by tissue or disease type and finding associated CpG or genes, visualization of cis- and trans-eQTMs through genome browser, heatmap interfaces across various tissues, and cohort-level data downloads. By integrating eQTM results with EWAS resources, the eQTM Atlas enables users to connect disease- or trait-associated CpGs to statistically associated genes rather than relying solely on proximity-based gene annotation, supporting functional interpretation of EWAS findings and generation of disease-specific regulatory hypotheses. Availability and implementationThe eQTM Atlas is freely available at https://shiny.crc.pitt.edu/eqtm_browser/. The web interface is implemented in R Shiny and hosted through the University of Pittsburgh Center for Research Computing (CRC). Source code is available at https://github.com/ads303/eQTM-Atlas.

genetics↗

sigNATURE maps cohort-specific T-cell states to reproducible programs of ICI response

Immune checkpoint inhibitors (ICIs) can induce durable responses across cancers, yet T-cell biomarkers of response remain difficult to reproduce across single-cell RNA-seq studies. A major reason is that T-cell states are typically defined de novo within each cohort, making reported marker genes sensitive to cohort composition and analytic choices rather than stable cellular programs. Here we present sigNATURE (signature Normalization and Atlas-based T-cell Understanding for Reproducibility and Evaluation), a reference-guided framework that maps query cells onto large CD4+ and CD8+ T-cell atlases, evaluates published ICI-response markers in an atlas-aligned coordinate system, and quantifies the atlas support of mapped cells through a cell-level identifiability score. We applied sigNATURE to two independent ICI scRNA-seq cohorts comprising 36 non-small cell lung cancer patients and 15 skin cancer patients (11 basal cell carcinoma and 4 squamous cell carcinoma). Across cohorts, sigNATURE-derived features more robustly resolved response-associated T-cell structure than cohort-derived state definitions, yielding clearer unsupervised separation of responders and non-responders, enabling integrated analysis of independent studies in a shared atlas-aligned space, and improving mean response-prediction AUC from 0.469 to 0.746. Using identifiability score, we further identify terminally differentiated effector CD8+ T cells and regulatory CD4+ T cells as prominent response-associated states across studies, prioritizing published markers in terms of robust, atlas-resolvable cell states. Using this framework. Together, these results establish sigNATURE as a framework for improving the reproducibility, cross-cohort comparability, and mechanistic interpretability of single-cell ICI biomarkers.

immunology↗

Contrastive Alignment of Expression and Copy Number Highlights Dosage-Insensitive Genes in Cancer

Copy number variations (CNVs) are a hallmark of cancer genomes, yet the relationship between CNV and gene expression is not strictly deterministic. Some genes maintain stable expression despite copy number changes through regulatory compensation. Identifying these dosage-insensitive genes is challenging, requiring methods that distinguish true regulatory escape from technical noise in heterogeneous single-cell data. Here, we present a contrastive learning framework that learns a shared latent space aligning single-cell RNA-seq expression profiles with inferred CNV patterns. Our key innovation is hard negative mining: explicitly training on cell pairs with similar CNV but divergent expression patterns, which represent potential dosage insensitivity. By combining InfoNCE loss with hard negative triplet loss, we learn embeddings where expression-CNV distance quantifies regulatory concordance. We apply this framework to 10 lung adenocarcinoma patients (80k cells) from the GSE131907 atlas, classifying cancer cells as "concordant" (expression follows CNV) or "discordant" (expression escapes CNV). Differential expression analysis between these groups reveals two gene categories: escape genes upregulated in discordant cells despite CNV status, and compensation genes downregulated in discordant cells. Pooled analysis across 40,775 cancer cells identifies significant escape genes including VSIG4, FCGR1A, TREM2, and MARCO, as well as compensation genes such as MALAT1, CCL5, and CD8A. These genes represent candidate therapeutic targets and biomarker hypotheses for CNV-independent tumor behavior. Our approach provides a generalizable frame-work for discovering regulatory escape mechanisms in cancer using standard single-cell RNA-seq data.

genomics↗

Systemic and Local Delivery of siRNA to the CNS and Periphery via Anti-IGF1R Antibody Conjugation

siRNA delivery platforms capable of accessing both central and peripheral tissues are critically needed to expand the therapeutic potential of oligonucleotides. To address this, we developed a novel siRNA-antibody conjugate by attaching an Hprt-targeting siRNA to an engineered antibody shuttle. This shuttle targets the insulin-like growth factor 1 receptor (IGF1R) using a fused antibody fragment (Clone F) and utilizes an antibody backbone with no tissue-relevant binding in this study. The resulting conjugate, designated Clone F-Hprt, demonstrated robust in vivo knockdown across multiple tissues. Clone F-Hprt demonstrated enhanced penetration into central nervous system (CNS) tissues compared to unconjugated siRNA following intracerebroventricular (ICV) and intravenous (IV) administration. In peripheral tissues, Clone F-Hprt achieved widespread knockdown in muscle, heart, and lung, consistent with IGF1R expression. The conjugate was well tolerated across all routes, including with repeated dosing. Although several receptor-mediated approaches for CNS delivery are progressing to the clinic (e.g., targeting the transferrin receptor), clinical validation remains to be demonstrated. Our findings highlight IGF1R as an alternative receptor capable of supporting delivery across both central and peripheral tissues, offering a complementary strategy for expanding the therapeutic landscape of oligonucleotide delivery.

neuroscience↗

The Role of Pavlovian Bias in Smoking Cessation Success and Neurocognitive Alterations During Nicotine Withdrawal

BackgroundInability to manage conflicts between multiple decision-making systems is associated with various mental disorders including addiction. The imbalance between the Pavlovian and instrumental systems may contribute to smoking cessation failure and relapse, as excessive Pavlovian motivation may override goal-directed quitting attempts. However, the exact role of the Pavlovian bias in smoking cessation and its neurocognitive mechanisms remain poorly understood. MethodsEighty-six smokers participated in a smoking cessation clinic, completing the well-established orthogonalized go-nogo task before and after the intervention. We applied computational modeling and functional magnetic resonance imaging (fMRI) analyses to investigate the role of Pavlovian bias and its neural correlates in predicting smoking cessation outcomes. ResultsComputational modeling revealed that higher levels of Pavlovian bias were associated with treatment failures. Importantly, Pavlovian bias significantly moderated the relationship between clinic participation rate and the likelihood of smoking cessation, suggesting that such bias can undermine motivational effort to quit. Furthermore, individuals who successfully quit smoking exhibited increased Pavlovian bias toward reward following cessation, indicating a potential cognitive mechanism underlying the relapse cycle. Complementary fMRI analyses demonstrated that Pavlovian bias influenced valence encoding in the ventromedial prefrontal cortex (vmPFC), suggesting altered decision-making neural circuits. ConclusionsPavlovian bias can be a critical risk factor of relapse in the smoking population, while this bias can be increased in response to nicotine abstinence. Moreover, the results highlight the roles of the vmPFC in decision-making under Pavlovian-instrumental conflict, providing insights into the neural underpinnings of relapse vulnerability. Understanding these mechanisms may guide targeted interventions to enhance smoking cessation outcomes.

neuroscience↗

Dynamic Brain Network Changes Associated with Successful Smoking Cessation

BackgroundTobacco smoking continues to be a leading cause of preventable morbidity and mortality globally, with the success rate of unaided cessation remaining consistently low. Understanding the neurobiological mechanisms of smoking cessation is crucial for improving quit rates. However, there has been a lack of studies examining brain network changes associated with smoking cessation over time. In this study, we aimed to investigate longitudinal changes in the functional connectivity (FC) of large-scale brain networks underlying smoking cessation outcomes using resting-state functional magnetic resonance imaging (fMRI). MethodsA total of 98 treatment-seeking smokers participated in a 6-week cessation program and underwent resting-state fMRI scans before and after the intervention. Independent component analysis identified the salience network (SN), executive control network (ECN), and default mode network (DMN) components, and region of interest (ROI)-to-ROI FC was compared between successful and unsuccessful quitters using a group x time mixed-effects model. Correlations with smoking-related measures were explored. ResultsSignificant group-by-time interaction effects were found in FC, particularly involving connections between SN and ECN, as well as between the SN and DMN. Specifically, successful quitters exhibited greater baseline FC in the SN-ECN and SN-DMN circuits, which tended to normalize during the cessation process. Exploratory correlational analyses revealed trends suggesting that stronger pre-quit connectivity between the SN and ECN was associated with greater withdrawal severity and longer smoking history in successful quitters. ConclusionsTaken together, the normalization of initially elevated pre-quit FC in SN-ECN and SN-DMN circuits may reflect an adaptive neural process that supports successful withdrawal management and attentional reallocation during cessation. The identification of these neural substrates not only enhances our mechanistic understanding of smoking cessation over time but also underscores the need for targeted interventions that focus on these neural circuits to enhance quit outcomes.

neuroscience↗

DeepDiff-SHAP: Interpretable deep learning for subgroup-specific causal inference using conditional SHAP

Precision medicine aims to tailor healthcare strategies to individual differences in genetic, clinical, and environmental factors. However, identifying subgroup-specific causal relationships in complex biomedical data remains a major challenge, especially when standard causal inference methods average over population heterogeneity. We introduce DeepDiff-SHAP, a novel framework that combines regression-based and deep learning-based differential causal inference to detect changes in causal relationships across patient subgroups. DeepDiff-SHAP integrates SHapley Additive exPlanations (SHAP) to estimate conditional dependencies and perform nonlinear differential causal inference in a principled, interpretable manner. Applying DeepDiff-SHAP to two population-scale datasets, the CDC Diabetes Health Indicators Dataset and a UK Biobank sepsis cohort stratified by hypertension, we identified clinically meaningful and subgroup-specific causal changes in relationships between features such as age, general health, alkaline phosphatase, and cholesterol. Our results demonstrate that deep learning enhances sensitivity to complex interaction patterns overlooked by linear models, providing new biological insights into disease progression and comorbidity-specific risk mechanisms. DeepDiff-SHAP offers a scalable and interpretable solution to uncover individualized causal pathways, advancing the goal of truly personalized medicine.

bioinformatics↗

AIVE: accurate predictions of SARS-CoV-2 infectivity from comprehensive analysis

An unprecedented amount of SARS-CoV-2 data has been accumulated compared with previous infectious diseases, enabling insights into its evolutionary process and more thorough analyses. This study investigates SARS-CoV-2 features as it evolved to evaluate its infectivity. We examined viral sequences and identified the polarity of amino acids in the Receptor Binding Motif (RBM) region. We detected an increased frequency of amino acid substitutions to lysine (K) and arginine (R) in Variants of Concern (VOCs). As the virus evolved to Omicron, commonly occurring mutations became fixed components of the new viral sequence. Furthermore, at specific positions of VOCs, only one type of amino acid substitution and a notable absence of mutations at D467 was detected. We found that the binding affinity of SARS-CoV-2 lineages to the ACE2 receptor was impacted by amino acid substitutions. Based on our discoveries, we developed APESS, an evaluation model evaluating infectivity from biochemical and mutational properties. In silico evaluation using real-world sequences and in vitro viral entry assays validated the accuracy of APESS and our discoveries. Using Machine Learning, we predicted mutations that had the potential to become more prominent. We created AIVE, a web-based system, accessible at https://ai-ve.org to provide infectivity measurements of mutations entered by users. Ultimately, we established a clear link between specific viral properties and increased infectivity, enhancing our understanding of SARS-CoV-2 and enabling more accurate predictions of the virus.

genomics↗

Increased inflammatory signature in myeloid cells of non-small cell lung cancer patients with high clonal hematopoiesis burden

Clonal hematopoiesis of indeterminate potential (CHIP) allows estimation of clonal dynamics and documentation of somatic mutations in the hematopoietic system. Recent studies utilizing large cohorts of the general population and patients have revealed significant associations of CHIP burden with age and disease status, including in cancer and chronic diseases. An increasing number of cancer patients are treated with immune checkpoint inhibitors (ICI), but the association of ICI response in non-small cell lung cancer (NSCLC) patients with CHIP burden remains to be determined. We collected blood samples from 100 metastatic NSCLC patients before and after ICI for high-depth sequencing of the CHIP panel and 63 samples for blood single-cell RNA sequencing(scRNA-seq). Whole exome sequencing (WES) was performed in an independent replication cohort of 180 patients. The impact of CHIP status on the immunotherapy response was not significant. However, metastatic lung cancer patients showed higher CHIP prevalence (44/100 for patients vs 5/42 for controls; P = 0.01). In addition, lung squamous cell carcinoma patients showed increased burden of larger clones compared to lung adenocarcinoma patients (8/43 for LUSC vs 2/50 for LUAD; P = 0.04). Furthermore, single cell RNA-seq analysis of the matched patients showed significant enrichment of inflammatory pathways mediated by NF-B in myeloid clusters of the severe CHIP group. Our findings suggest minimal involvement of CHIP mutation and clonal dynamics during immunotherapy but a possible role of CHIP as an indicator of immunologic response in NSCLC patients.

genomics↗

Methyl-TWAS: A powerful method for in silico transcriptome-wide association studies (TWAS) using long-range DNA methylation

In silico transcriptome-wide association studies (TWAS) are commonly used to test whether expression of specific genes is linked to a complex trait. However, genotype-based in silico TWAS such as PrediXcan, exhibit low prediction accuracy for a majority of genes because genotypic data lack tissue- and disease-specificity and are not affected by the environment. Because methylation is tissue-specific and, like gene expression, can be modified by environment or disease status, methylation should predict gene expression with more accuracy than SNPs. Therefore, we propose Methyl-TWAS, the first approach that utilizes long-range methylation markers to impute gene expression for in silico TWAS through penalized regression. Methyl-TWAS 1) predicts epigenetically regulated/associated expression (eGReX), which incorporates tissue-specific expression and both genetically- (GReX) and environmentally-regulated expression to identify differentially expressed genes (DEGs) that could not be identified by genotype-based methods; and 2) incorporates both cis- and trans- CpGs, including various regulatory regions to identify DEGs that would be missed using cis-methylation only. Methyl-TWAS outperforms PrediXcan and two other methods in imputing gene expression in the nasal epithelium, particularly for immunity-related genes and DEGs in atopic asthma. Methyl-TWAS identified 3,681 (85.2%) of the 4,316 DEGs identified in a previous TWAS of atopic asthma using measured expression, while PrediXcan could not identify any gene. Methyl-TWAS also outperforms PrediXcan for expression imputation as well as in silico TWAS in white blood cells. Methyl-TWAS is a valuable tool for in silico TWAS, leveraging a growing body of publicly available genome-wide DNA methylation data for a variety of human tissues.

bioinformatics↗

Sprr1 and miR-130b contribute to the senescence-like phenotype in aging

Aging is an inevitable process with senescence being one of its hallmarks. Recent advances have indicated that the elimination of senescent cells can reduce the signs of aging and increase healthy life span. Here, we identify a negative modulator of aging, Sprr1a, and in turn a negative modulator of Sprr1a, miR-130b. We show that reductions in Sprr1a levels, including via miR-130b expression, promotes cell senescence-like phenotype. We find that mediators of senescence, such as inflammatory cytokines and cell cycle regulators, are modulated by the miR-130b and Sprr1a-related pathway. For example, the levels of p16, p53 and p21 become decreased or increased upon the respective expression of Sprr1a versus miR-130b. Further, as shown in relation to p16 levels and {beta}-galactosidase levels, cells expressing Sprr1a exhibit significant protection from senescence-inducing factors such as radiation or Doxorubicin, suggesting that Sprr1a might contribute to protection against age-related pathologies. Taken together, we introduce two modulators of properties associated with senescence-like phenotype.

molecular biology↗

Methylglyoxal is the main culprit to impairing neuronal function: mediated through tryptophan depletion.

Depression is a common and prevalent illness and the exact cause of major depressive disorder is not known. Here, we investigated how methylglyoxal (MGO) stress induces depression and unveiled the potential molecular mechanism. Our in vivo results suggested that MGO caused depression in mice, confirmed by several behavioral tests. Interestingly, it halted the mices brains tryptophan levels and its related neurotransmitters. In addition, MGO induced a reduction in the number of cells in different hippocampal regions. Moreover, it decreased tryptophan hydroxylase 1 (TPH1) and tryptophan hydroxylase 1 (TPH2) levels in the brain and large intestine. Surprisingly, MGO showed the highest affinity and trapping ability toward tryptophan. Most importantly, combined treatment with MGO-tryptophan displayed similar effects as those exhibited by the tryptophan-null treatment in neuronal cells, which included neuronal apoptosis, decrease TPH1 and TPH2 levels, and inhibition of neuronal outgrowth. However, tryptophan treatment improved MGO induced depression-like behavior of mice and recovered the loss of neuronal and hippocampal cells. Subsequently, it also induced MGO detoxifying factors, tryptophan levels, and reduces inflammation in the intestine. Collectively, our data revealed that MGO induced depression facilitated by neuronal and synaptic dysfunction is mediated through the disturbance of tryptophan metabolism in the brain and intestine.

neuroscience↗

Condition for successful artificial selection on microbial collectives and optimal experimental setup

Collectives, such as microbial communities, can perform functions beyond the capability of individual members. Enhancing these collective functions through artificial selection, however, presents significant challenges. Here, we explore the rafting-a-waterfall phenomenon, a metaphor illustrating how the success in achieving a target population composition in microbial collectives depends on both the target characteristics and initial conditions. Specifically, collectives comprising fast-growing (F) and slow-growing (S) individuals were grown for a period of "maturation" time, and the collective with S-frequency closest to the target value is chosen to "reproduce" (inoculate) offspring collectives. Such collective selection is dictated by two opposing forces: during collective maturation, intra-collective selection acts like a waterfall, relentlessly driving the S-frequency to lower values, while during collective reproduction, inter-collective selection resembles a rafter striving to reach the target frequency. Due to this model structure, maintaining a target frequency requires the continued action of inter-collective selection. Using simulations and analytical calculations, we show that intermediate target S frequencies are the most challenging, akin to a target within the vertical drop of a waterfall, rather than above or below it. This arises because intra-collective selection is the strongest at intermediate S-frequencies, which can overpower inter-collective selection. While achieving low target S frequencies is consistently feasible, attaining high target S-frequencies requires an initially high S-frequency -- much like a raft that can descend but not ascend a waterfall. The range of attainable target frequencies depends on the initial population size of the collectives: as the population size in Newborn collectives increases, the region of achievable target frequency is reduced until no frequency is achievable. In contrast, the number of collectives under selection plays a less critical role. In scenarios involving more than two populations, the evolutionary trajectory must navigate entirely away from the metaphorical waterfall drop. Our findings illustrate that the strength of intra-collective evolution is frequency-dependent, with implications in experimental planning.

evolutionary biology↗

Therapeutic resistance to FLT3 inhibition is driven by a novel ATM/mTOR pathway regulating oxidative phosphorylation

While leukemic cells are susceptible to various therapeutic insults, residence in the bone marrow microenvironment typically confers protection from a wide range of drugs. Thus, understanding the unique molecular changes elicited by the marrow is of critical importance towards improving therapeutic outcomes. In the present study, we demonstrate that aberrant activation of oxidative phosphorylation serves to induce therapeutic resistance in FLT3 mutant human AML cells challenged with FLT3 inhibitor drugs. Importantly, our findings show that AML cells are protected from apoptosis following FLT3 inhibition due to marrow-mediated activation of ATM, which in turn up-regulates oxidative phosphorylation via mTOR signaling. mTOR is required for the bone marrow stroma-dependent maintenance of protein translation, with selective polysome enrichment of oxidative phosphorylation transcripts, despite FLT3 inhibition. To investigate the therapeutic significance of this finding, we tested the mTOR inhibitor everolimus in combination with the FLT3 inhibitor quizartinib in primary human AML xenograft models. While marrow resident AML cells were highly resistant to quizartinib alone, the addition of everolimus induced profound reduction in tumor burden and prevented relapse. Taken together, these data provide a novel mechanistic understanding of marrow-based therapeutic resistance, and a promising strategy for improved treatment of FLT3 mutant AML patients.

cancer biology↗

A genome-edited β-cell model of Prader-Willi syndrome reveals chronic deficits in endoplasmic reticulum chaperones and insulin secretion

Prader-Willi syndrome (PWS) is a multisystem disorder with neurobehavioral, metabolic, and hormonal phenotypes, caused by loss of expression of a paternally-expressed imprinted gene cluster. Prior evidence from a PWS mouse model identified abnormal pancreatic islet development with retention of aged insulin and deficient insulin secretion. To determine the collective roles of PWS genes in {beta}-cell biology, we used genome-editing to generate isogenic, clonal INS-1 insulinoma lines having 3.16 Mb deletions of the silent, maternal (control) or active, paternal PWS-alleles. PWS {beta}-cells demonstrated a significant cell-autonomous reduction in basal and glucose-stimulated insulin secretion. Further, proteomic analyses revealed reduced levels of cellular and secreted hormones, including all insulin peptides and amylin, concomitant with reduction of at least ten endoplasmic reticulum (ER) chaperones, including GRP78 and GRP94. Critically, transcriptomic studies demonstrated that the broad reduction of ER chaperones originated from transcriptional downregulation without corresponding changes for Ins1 and Ins2. In contrast to the dosage compensation previously seen for ER chaperones in Grp78 or Grp94 gene knockouts or knockdown, compensation is precluded by the stress-independent deficiency of ER chaperones in PWS {beta}-cells. Consistent with reduced ER chaperones levels, PWS INS-1 {beta}-cells are more sensitive to ER stress, leading to earlier activation of all three arms of the unfolded protein response. These findings suggest that a chronic shortage of ER chaperones in PWS {beta}-cells leads to a deficiency of protein folding and/or delay in ER transit of insulin and other cargo. In summary, our results illuminate the pathophysiological basis of pancreatic {beta}-cell hormone deficits in PWS, with evolutionary implications for the multigenic PWS-domain, and indicate that PWS-imprinted genes coordinate concerted regulation of ER chaperone biosynthesis and {beta}-cell secretory pathway function.

genetics↗

A Calcium/Palmitoylation Switch Interfaces the Signaling Networks of Stress Response and Transition to Flowering

The precise timing of flowering in adverse environments is critical for plants to secure reproductive success. We report a novel mechanism controlling the time of flowering by which the palmitoylation-dependent nuclear import of protein SOS3/CBL4, a Ca2+-signaling intermediary in the plant response to salinity, results in the selective stabilization of the flowering time regulator GIGANTEA inside the nucleus under salt stress, while degradation of GIGANTEA in the cytosol releases the protein kinase SOS2 to achieve salt tolerance. S-acylation of SOS3 was critical for its nuclear localization and the promotion of flowering, but dispensable for salt tolerance. SOS3 interacted with the photoperiodic flowering components GIGANTEA and FKF1 on the CONSTANS gene promoter to sustain the transcription of CO and FT under salinity. Thus, SOS3 acts as a Ca2+- and palmitoylation-dependent molecular switch that fine-tunes flowering in a saline environment through the shared spatial separation and selective stabilization of GIGANTEA. The SOS3 protein connects two signaling networks to co-regulate stress adaptation and time of flowering. Short summaryS-acylation promoted the nuclear import of SOS3/CBL4 for the selective stabilization of the photoperiodic floral regulator GIGANTEA to fine-tune flowering time in a saline environment. Spatial separation of SOS3 acts as a molecular switch co-regulating stress adaptation and time of flowering.

plant biology↗