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Wang, G.

Publications and source records attributed to Wang, G..

At least 289 records · Page 16Linked to original sources
bioRxiv2022

The repertoire of copy number alteration signatures in human cancer

Copy number alterations (CNAs) are a predominant source of genetic alterations in human cancer and play an important role in cancer progression. However comprehensive understanding of the mutational processes and signatures of CNA is still lacking. Here we developed a mechanism-agnostic method to categorize CNA based on various fragment properties, which reflect the consequences of mutagenic processes and can be extracted from different types of data, including whole genome sequencing (WGS) and SNP array. The 14 signatures of CNA have been extracted from 2778 pan-cancer analysis of whole genomes (PCAWG) WGS samples, and further validated with 10851 the cancer genome atlas (TCGA) SNP array dataset. Novel patterns of CNA have been revealed through this study. The activities of some CNA signatures consistently predict cancer patients prognosis. This study provides a repertoire for understanding the signatures of CNA in cancer, with potential implications for cancer prognosis, evolution, and etiology.

bioinformatics↗
bioRxiv2022

Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex

The relationship between genetic variation and gene expression in individual brain cell types and subtypes has remained elusive. Here, we generated single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of 424 individuals of advanced age; analyzing 1.5 million nuclear transcriptomes, we assessed the effect of genetic variants on RNA expression in cis (cis-eQTL) for 7 cell types and 81 cell subtypes. This effort identified 10,004 eGenes at the cell type level and 8,138 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer pathology, accounting for the effect of APOE{varepsilon}4, providing mechanistic insights into both pathologies. While eQTLs are readily detected, only a TMEM106B variant robustly affects the proportion of cell subtypes. Integration of these results with GWAS highlighted the targeted cell type and likely causal gene within susceptibility loci for Alzheimers, Parkinsons, schizophrenia, and educational attainment.

genomics↗
bioRxiv2022

Size-Dependent Transport of Cerebrospinal Fluid Tracers in Mouse Brain Observed by Dynamic Contrast-Enhanced MRI

Recent studies have suggested the glymphatic system as a key mechanism of waste removal in the brain. Dynamic contrast-enhanced MRI (DCE-MRI) using intracisternally administered contrast agents is a promising tool for assessing glymphatic function in the whole brain. In this study, we evaluated the transport kinetics and distribution of three MRI contrast agents with vastly different molecular sizes in mice. Our results demonstrate that oxygen-17 enriched water (H217O), which has direct access to parenchymal tissues via aquaporin-4 water channels, exhibited significantly faster and more extensive transport compared to the two gadolinium-based contrast agents (Gd-DTPA and GadoSpin). Time-lagged correlation and clustering analyses also revealed different transport pathways for Gd-DTPA and H217O. Furthermore, there were significant differences in transport kinetics of the three contrast agents to the lateral ventricles, reflecting the differences in forces that drive solute transport in the brain. These findings suggest the size-dependent transport pathways and kinetics of intracisternal contrast agents and the potential of DCE-MRI for assessing multiple aspects of solute transport in the glymphatic system.

neuroscience↗
bioRxiv2022

The Effect of Node Features on GCN-based Brain Network Classification: An Empirical Study

Brain functional network (BFN) analysis has become a popular technique for identifying neurological/mental diseases. Due to the fact that BFN is a graph, graph convolutional network (GCN) can be naturally used in the classification of BFN. Different from traditional methods that directly use the adjacency matrices of BFNs to train a classifier, GCN requires an additional input -- node features. To our best knowledge, however, there is no systematic study to analyze their influence on the performance of GCN-based brain disorder classification. Therefore, in this per, we conduct an empirical study on various node feature measures, including 1) original fMRI signals, 2) one-hot encoding, 3) node statistics, 4) node correlation, and 5) their combination. Experimental results on two benchmark databases show that different node feature inputs to GCN significantly affect the brain disease classification performance, and node correlation usually contributes higher accuracy compared to original signals and manually extracted statistical features.

neuroscience↗
bioRxiv2022

Curvature Sensing and Membrane Remodeling of the VPS37A N-terminal Domain during Autophagy

VPS37A, a component of ESCRT-I, is essential for recruiting a subset of ESCRT proteins that seal the phagophore during autophagosome biogenesis. In this study, we uncover two hydrophobic motifs in the VPS37A N-terminal 148 amino acids (VPS37A1-148) that selectively interact with highly curved membranes. Mutations in these motifs nearly abolish VPS37A membrane binding in vitro and compromise its localization to the phagophore and autophagic flux in vivo. We also determined the solution structure of residues 21 to 131 and demonstrated that it is the UEVL (ubiquitin E2 variant-like) domain. Intriguingly, this domain remodels highly curved liposomes to high-order structures. We suggest that the specific interactions between VPS37A1-148 and the curved membrane may facilitate the recruitment of VPS37A to the phagophore and its subsequent closure. Our results support the premise that the distinct membrane architecture of the cup-like phagophore spatiotemporally regulates autophagosome biogenesis.

biochemistry↗
bioRxiv2022

Spatiotemporal gene expression atlas of the extremophyte Schrenkiella parvula

Extremophytes are naturally selected to survive environmental stresses, but scarcity of genetic resources for them developed with spatiotemporal resolution limit their use in stress biology. Schrenkiella parvula is one of the leading extremophyte models with initial molecular genomic resources developed to study its tolerance mechanisms to high salinity. Here we present a transcriptome atlas for S. parvula with subsequent analyses to highlight its diverse gene expression networks associated with salt responses. We included spatiotemporal expression profiles, expression specificity of each gene, and co-expression and functional gene networks representing 115 transcriptomes sequenced from 35 tissue and developmental stages examining their responses before and after 27 salt treatments in our current study. The highest number of tissue-preferentially expressed genes were found in seeds and siliques while genes in seedlings showed the broadest expression profiles among developmental stages. Seedlings had the highest magnitude of overall transcriptomic responses to salinity compared to mature tissues and developmental stages. Differentially expressed genes in response to salt were largely mutually exclusive but shared common stress response pathways spanning across tissues and developmental stages. Our foundational dataset created for S. parvula representing a stress-adapted wild plant lays the groundwork for future functional, comparative, and evolutionary studies using extremophytes aiming to uncover novel stress tolerant mechanisms. SIGNIFICANCE STATEMENTConcerted transcriptomic responses coordinated across developmental stages and tissues are required to complete a plant lifecycle under salt stress. Transcriptomic resources created with spatiotemporal resolution for plants are rare and for stress-adapted plants rarer. We present a transcriptome atlas enabling discovery of genes and networks evolved as adaptations to salt stress in a model extremophyte, Schrenkiella parvula. The spatiotemporally resolved gene expression networks are largely non-overlapping but functionally connected through synergistic stress responsive pathways.

plant biology↗
bioRxiv2022

The Hairpin Basis for the Structural Thermostablity and the Functional Thermoactivity of Aldolase B

Thermostability is important for thermoactivity of proteins including enzymes. However, it is still challenging to pinpoint the specific structural factors for different temperature thresholds to initiate their specific structural and functional perturbations. Here, graph theory was used to investigate how the temperature-dependent noncovalent interactions as identified in the structures of aldolase B and its prevalent A149P mutant could form a systematic fluidic grid-like mesh network with topological grids to regulate the structural thermostability and the functional thermoactivity. The results showed that the biggest grid may determine the temperature thresholds for the changes in their secondary and tertiary structures and specific catalytic activities. Further, a highly conserved thermostable grid may serve as an anchor to secure the flexible active site to achieve the specific thermoactivity. Finally, higher grid-based systematic thermal instability may disfavor the thermoactivity. Thus, this computational study may provide critical clues for the structural thermostability and the functional thermoactivity of proteins including enzymes.

biochemistry↗
bioRxiv2022

The glyoxylate shunt protein ICL-1 protects from mitochondrial superoxide stress through activation of the mitochondrial unfolded protein response.

Eliminating mitochondrial superoxide dismutase (SOD) causes neonatal lethality in mice and death of flies within 24 hours after eclosion. Deletion of mitochondrial sod genes in C. elegans impairs fertility as well, but surprisingly is not detrimental to survival of progeny generated. The comparison of metabolic pathways among mouse, flies and nematodes reveals that mice and flies lack the glyoxylate shunt. Here we show that ICL-1, the only protein of the glyoxylate shunt, is critical for protection against embryonic lethality resulting from elevated levels of mitochondrial superoxide. In exploring the mechanism by which ICL-1 protects against ROS-mediated embryonic lethality, we find that ICL-1 is required for the efficient activation of mitochondrial unfolded protein response (UPRmt) and that the UPRmt is essential to suppress embryonic/neonatal lethality in animals lacking mitochondrial SOD. In sum, we identified a biochemical pathway that highlights a molecular strategy for combating superoxide consequences in cells.

biochemistry↗
bioRxiv2022

Analysis of sex differential genes at whole genome level reveals their organ- and chromosome-dependent expressions, regulations, and interactions

Males and females possess genomes that are almost identical but differ in morbidity, prevalence, severity, response to therapies and mortality of many diseases. We comprehensively analyzed gene expression data in seven tissues from BXD recombinant inbred (RI) mouse strains. We found that there were considerable differences in the numbers and functions among different tissues and between autosomal and sex chromosomes. Among sex differential genes, those on autosomal chromosomes mainly function to regulate metabolic pathways related to their host organs, while those on sex chromosomes mainly regulate nuclear proteins required for DNA replication or transcription during early development. Kidney possessed the fewest sex differential genes on sex chromosomes. The sexually dimorphic genes expressed on X chromosomes were all related to perception, while genes on the autosomal chromosomes were related to metabolism. These patterns of gene expression do not translate into similarity of protein structures, rather they are grouping with function.

cell biology↗
bioRxiv2022

Improving stem cell-derived pancreatic islets using single-cell multiome-inferred regulomes

Pancreatic islet cells derived from human pluripotent stem cells hold great promise for modeling and treating diabetes. Differences between stem cell-derived and primary islets remain, but molecular insights to inform improvements are limited. Here, we acquire single-cell transcriptomes and accessible chromatin profiles during in vitro islet differentiation and pancreas from childhood and adult donors for comparison. We delineate major cell types, define their regulomes, and describe spatiotemporal gene regulatory relationships between transcription factors. CDX2 emerged as a regulator of enterochromaffin-like cells, which we show resemble a transient, previously unrecognized, CDX2+ pre-{beta}-cell population in fetal pancreas, arguing against a proposed non-pancreatic origin. Furthermore, we observe insufficient activation of signal-dependent transcriptional programs during in vitro {beta}-cell maturation and identify sex hormones as drivers of {beta}-cell proliferation in childhood. Altogether, our analysis provides a comprehensive understanding of cell fate acquisition in stem cell-derived islets and a framework for manipulating cell identities and maturity.

cell biology↗
bioRxiv2022

Seq2Neo: a comprehensive pipeline for cancer neoantigen im-munogenicity prediction

Neoantigens derived from somatic DNA alterations are ideal cancer-specific targets. In recent years, the combination therapy of PD-1/PD-L1 blockers and neoantigen vaccines shows clinical efficacy in original PD-1/PD-L1 blocker non-responders. However, not all somatic DNA mutations can result in immunogenicity in cancer cells, and efficient tools for predicting the immunogenicity of neoepitope are still urgently needed. Here we present the Seq2Neo pipeline, which provides a one-stop solution for neoepitope features prediction from raw sequencing data, and neoantigens derived from different types of genome DNA alterations, including point mutations, insertion deletions, and gene fusions are supported. Importantly a convolutional neural networks (CNN) based model has been trained to predict the immunogenicity of neoepitope. And this model shows improved performance compared with currently available tools in immunogenicity prediction in independent datasets. We anticipate that the Seq2Neo pipeline will become a useful tool in prediction of neoantigen immunogenicity and cancer immunotherapy. Seq2Neo is an open-source software under an academic free license (AFL) v3.0 and it is freely available at https://github.com/XSLiuLab/Seq2Neo.

bioinformatics↗
bioRxiv2022

Drivers of interlineage variability in mitogenomic evolutionary rates in flatworms (Platyhelminthes) are multifactorial

The forces driving interlineage variability in the evolutionary rates (both sequence and architecture) of mitochondrial genomes are often inconsistent and unpredictable. Herein we studied the impacts of multiple variables using 223 flatworm (Platyhelminthes) species and phylogenetic multilevel regression models. We found that: 1. Mitogenomic sequence evolution is faster in parasites associated with the thermally stable environment of endothermic hosts, but the overall impact of thermic habitat is small; 2. Mitogenome sizes are smaller in parasites of endothermic hosts, but the effects are small and inconsistent; 3. Mitogenomic gene order rearrangements (GORR) are positively correlated with mitogenomic size; 4. The expected positive correlation between GORR and sequence evolution is lineage-specific, and non-parasitic species exhibited a strong negative correlation; 5. Longevity has negligible impacts on mitogenomic evolution; 6. Parasitic (Neodermata) flatworm lineages exhibit higher evolutionary rates than non-parasitic lineages; 7. The effective population size has negligible impacts on mitogenomic evolution; 8. Comparatively, parasitism had by far the greatest impact on the mitogenomic evolution, but due to the monophyletic origin of this life-history strategy, alternative hypotheses cannot be rejected. A large number of factors impact the mitogenomic evolution in flatworms, with lineage-specific relative contributions, which sometimes produces incongruent lineage-specific mitogenomic evolution patterns.

evolutionary biology↗
bioRxiv2022

Meningeal IL-17 producing T cells mediate cognitive impairment in salt-sensitive hypertension

Hypertension, a disease afflicting over one billion individuals worldwide, is a leading cause of cognitive impairment, the mechanisms of which remain poorly understood. In a mouse model of hypertension, we found that the neurovascular and cognitive dysfunction depends on IL-17, a cytokine elevated in hypertensive individuals. However, neither circulating IL-17 or brain angiotensin signaling could account in full for the dysfunction. Rather, IL-17 produced by T-cells in the dura mater was the major culprit by reaching the cerebrospinal fluid and activating IL-17 receptors on brain associated macrophages. Accordingly, depleting brain macrophages, deleting IL17-RA in brain macrophages, or suppressing meningeal T cells completely rescued cognitive function without attenuating blood pressure elevation, circulating IL-17 or brain angiotensin signaling. The data unveil a critical role of meningeal T-cells and macrophage IL-17 signaling in the neurovascular and cognitive dysfunction of hypertension and suggest novel therapies to counteract the devastating effects of hypertension on cognitive health.

neuroscience↗
bioRxiv2022

MAM-STAT3-induced upregulation of mitochondrial Ca+2 causes immunosenescence in patients with type A mandibuloacral dysplasia

Homozygous lamina/c p.R527C mutations result in severe mandibuloacral dysplasia (MAD) and progeroid syndrome, but the underlying molecular pathology remains unknown. Here, we report on three patients with MAD, all displaying severe systemic inflammaging and characterized the major molecular pathways involved in the manifestation of this disease. Analysis of induced pluripotent stem cell (IPSC)-derived mesenchymal stem cells (MAD-iMSCs) obtained from the patients revealed that increased mitochondrial Ca+2 loading was the root cause of lost mitochondrial membrane potential, abnormal fission/fusion and fragmentation, which then participated in inflammaging by inducing the inflammasome. These alterations in Ca+2 homeostasis were mediated by signal transducer and activator of transcription 3 (STAT3), which is located on the mitochondrial associated membrane (MAM). STAT3 function could be rescued by treatment with clinically-approved IL-6 blockers, or by correction of R527C mutations. In addition, extracellular vesicles (EVs) obtained from MAD-iMSCs displayed reduced immunomodulatory function, being unable to rescue bleomycin-induced lung fibrosis and triggering mitochondrial dysfunction, senescence, and fibrosis in healthy cells. Our results provide new insights into the pathology of complex lamin-associated MAD with systemic immunosenescence, and suggest that targeting defective mitochondrial Ca+2 homeostasis may represent a promising novel therapy for this condition.

cell biology↗
bioRxiv2022

Organoid-based single-cell spatiotemporal gene expression landscape of human embryonic development and hematopoiesis

Single-cell level characterization of embryonic development is a major benchmark of human developmental biology. Spatiotemporal analysis of stem-cell-derived embryos offers conceptual and technical advances in the field. Here, we defined the single-cell spatiotemporal gene expression landscape of human embryonic development with stem-cell-derived organoids. We established the human embryonic organoid (HEMO) from expanded potential stem cells and achieved both embryonic and extraembryonic tissues in the same organoid. Time-series single-cell RNA sequencing paired with single-cell resolution spatial revealed human embryonic development signatures such as extraembryonic placenta, yolk sac hematopoiesis neural crest, blood vessels, and cardiac mesoderm. Hematopoietic tissues eventually predominated HEMO with erythropoiesis, mekagaryopiesis, and myelopoiesis. Cell-cell communication network analysis demonstrated that trophoblast-like tissues supplied WNT signaling in neural crest cells to facilitate maturation and migration. Single-cell resolution spatial transcriptomics defined the yolk sac erythro-megakaryopoietic niche. Vitronectin-integrin signaling, a major contributor to megakaryocyte maturation, was predominant in the yolk sac niche in HEMO and to human fetal samples. Overall, our study advances the spatiotemporal analysis of human embryonic development in stem-cell-derived organoids. HighlightsO_LIModeling human embryonic development from stem cells C_LIO_LIUsed of both 10X Chromium and 10X Visium to define the gene expression landscape of embryonic development and hematopoiesis C_LIO_LIWNT signaling as a regulator of neural crest maturation and EMT C_LIO_LIVTN-ITGA2B as the main contributor to Mk maturation within the yolk sac erythro-megakaryopoietic niche C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=158 HEIGHT=200 SRC="FIGDIR/small/505700v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1710d00org.highwire.dtl.DTLVardef@10ca8e0org.highwire.dtl.DTLVardef@2310d1org.highwire.dtl.DTLVardef@252728_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗
bioRxiv2022

Partitioning genetic effects on birth weight at classical human leukocyte antigen loci into indirect maternal and direct fetal components using structural equation modelling

Birth weight (BW), as a proxy for intrauterine growth, is influenced by both fetal and maternal genetic factors. Single nucleotide polymorphisms in the human leukocyte antigen (HLA) region in both maternal and fetal genomes have been robustly associated with BW in previous genetic association studies suggesting the involvement of classical HLA alleles in BW etiology. However, no study to date has partitioned the association between BW and classical HLA alleles into maternal and fetal components. We used structural equation modelling (SEM) to estimate the indirect maternal (i.e. via the intrauterine environment) and direct fetal effects of classical HLA alleles on BW. Our SEM leverages the data structure of the UK Biobank (UKB), which includes participants own BW and/or the BW of their firstborn child (in the case of UKB females). We show via simulation that our model yields asymptotically unbiased estimates of the maternal and fetal allelic effects on BW and appropriate type I error rates, in contrast to simple regression models that estimate unconditioned maternal and fetal effects. Asymptotic power calculations show that we have sufficient power to detect moderate-sized maternal or fetal allelic effects (standardized effect size [≥] 0.01) of common HLA alleles on BW in the UKB. Applying our SEM to imputed classical HLA alleles and own and offspring BW of [~]270,000 participants from the UKB replicated the previously reported association at the HLA-C locus (C*04:01, P = 2.13x10-7, C*05:01, P= 6.91x10-5, C*03:03, P= 4.53x10-3, respectively) and revealed strong evidence for maternal (HLA-A*03:01, P = 7.90x10-8; B*35:01, P = 7.78x10-5; B*39:06, P = 8.49 x10-5) and fetal allelic effects (HLA-B*39:06, P = 4.03x10-4) of non-HLA-C alleles on BW. These novel allelic associations between BW and classical HLA alleles provide insight into the immunogenetics of fetal growth in utero.

genetics↗
bioRxiv2022

Activation of Cerebellar Lobule VI PCTH+boxhMed Pathway Selectively blocks METH-induced Conditioned Place Preference in mice

The cerebellum is implicated in drug addiction. However, the cerebellar neuronal circuitry underlying addiction, especially classic pathway of Purkinje cells (PCs) to deep cerebellar nuclei (DCN), are largely unknown. Here, tracing experiments showed robust projections from the cerebellar lobule VI tyrosine hydroxylase (TH)-positive PCs (PCTH+) to CaMKII-positive glutamatergic neurons in medial cerebellar nucleus (MedCaMKII), forming PCTH+-MedCaMKII pathway. Then, mice were subjected to methylamphetamine (METH)-induced conditioned place preference (CPP), showing that METH exposure excited MedCaMKII and inhibited PCTH+. Silencing MedCaMKII by tettox suppressed the formation and expression of METH-induced CPP, but produced serious motor coordination deficits. Chemogenetic activation of lobule VI PCTH+-Med pathway during METH CPP training blocked the formation and expression of METH-induced CPP without affecting motor coordination, locomotor activity and sucrose reinforcements in mice. Our findings revealed a novel cerebellar lobule VI PCTH+-MedCaMKII pathway and pointed out is critical role in encoding METH-preferred behaviors.

neuroscience↗