Biology subjects

Wang, Y. A.

Publications and source records attributed to Wang, Y. A..

9 recordsLinked to original sources

bioRxiv2026

Identification of Bone Morphogenetic Protein 7 as a Master Regulator of Gastric Cancer-Associated Cachexia

Cachexia is a devastating and multifactorial syndrome characterized by progressive loss of body weight, skeletal muscle wasting, and systemic inflammation, frequently observed in patients with advanced gastric cancer (GC) with peritoneal dissemination. Despite its clinical significance, the molecular mechanisms underlying cancer-associated cachexia remain poorly understood. In this study, comparative transcriptomic analysis using the GEMINI database identified bone morphogenetic protein 7 (BMP7) as a novel candidate cachexia-inducing factor, along with the known cachexia mediators, growth differentiation factor 11 (GDF11) and growth differentiation factor 15 (GDF15). Functional studies demonstrated that BMP7 acts as an upstream regulator that drives cachectic phenotypes by inducing the expression of GDF11 and GDF15. Knockdown of BMP7, GDF11, or GDF15 in the cachexia-inducing GC cell line, MKN45 significantly attenuated weight loss and muscle wasting in vivo. Conversely, overexpression of BMP7 in the non-cachectic GC cell line, NUGC3 induced cachexia and upregulated GDF11 and GDF15 in tumor tissues. Furthermore, clinical analysis revealed that high BMP7 expression in tumor specimens from patients with advanced GC was associated with significantly poorer overall survival. These findings identify BMP7 as a master regulator of cancer-associated cachexia through the induction of GDF11 and GDF15 and suggest its potential as a promising therapeutic target for mitigating cachexia in GC.

cancer biology↗

bioRxiv2026

Multicopper oxidase mediated single-carbon insertion for skeletal remodeling

Modern drug discovery demands efficient strategies for generating structurally diverse compound libraries. Skeletal editing--a transformative paradigm enabling precise atom-level modifications within molecular frameworks, offers a sustainable alternative to traditional synthetic routes. While carbene insertion-mediated approaches have dominated single-carbon insertion strategies, current methodologies are limited by their reliance on hazardous, unstable carbene precursors and harsh reaction conditions. Herein, we report a multicopper oxidase (MCO)-catalyzed skeletal editing that enables the direct, one-step transformation of phenolic and indole derivatives into functionalized tropones and quinoline analogues through exogenous single-carbon insertion. This platform employs stable and safe nitroalkanes as carbon sources and O2 as the sole terminal oxidant. It accommodates a broad substrate scope and yields products with superior antibacterial activity against to multidrug-resistant strains relative to their parent compounds. This work introduces the first biocatalytic platform for exogenous single-carbon insertion skeletal editing. This sustainable and scalable strategy overcomes key limitations of synthetic approaches, offering efficient skeletal remolding and rapid expansion of bioactive compound libraries. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/714988v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@1f1d09borg.highwire.dtl.DTLVardef@b67c65org.highwire.dtl.DTLVardef@a0cd4dorg.highwire.dtl.DTLVardef@106afe5_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2025

Integrated Cross-Disease Atlas of Human And Mouse Astrocytes Reveals Heterogeneity and Conservation of Astrocyte Subtypes in Neurodegeneration

Astrocytes play a pivotal role in central nervous system homeostasis and neuroinflammation. Despite advancements in single-cell analyses, the heterogeneity of reactive astrocytes in neurodegenerative diseases, particularly across species, remains understudied. Here, we present an integrated atlas of 187,000 astrocytes from mouse models of Alzheimers (AD) and multiple sclerosis (MS) alongside 438,000 astrocytes from AD, MS, and Parkinsons (PD) patients. Our analysis identified four distinct mouse astrocyte clusters, including two disease-associated astrocyte (DAA) clusters, DAA1 and DAA2. DAA1 displayed reactivity resembling responses to acute stimuli, including endotoxemia, while DAA2 expressed well-known AD risk genes. In an AD model, DAA1 and DAA2 exhibited distinct spatial relationships to amyloid plaques. In humans, we identified eight distinct astrocyte clusters, encompassing homeostatic and disease-associated subtypes. Cross-species analysis linked disease-associated clusters while also highlighting divergent expression in others. Our astrocyte atlas is available through a user-friendly, searchable website: http://research-pub.gene.com/AstroAtlas/.

neuroscience↗

bioRxiv2024

SUV39H1 Preserves Cancer Stem Cell Chromatin State and Properties in Glioblastoma

Of the more than 100 types of brain cancer, glioblastoma (GBM) is the deadliest. As GBM stem cells (GSCs) are considered to be responsible for therapeutic resistance and tumor recurrence, effective targeting and elimination of GSCs could hold promise for preventing GBM recurrence and achieving potential cures. We show here that SUV39H1, which encodes a histone-3, lysine-9 methyltransferase, plays a critical role in GSC maintenance and GBM progression. Upregulation of SUV39H1 was observed in GBM samples compared to normal brain tissues, and knockdown of SUV39H1 in patient-derived GSCs impaired their proliferation and stemness. Single-cell RNA-seq analysis demonstrated restricted expression of SUV39H1 is in GSCs relative to non-stem GBM cells, likely due to super-enhancer-mediated transcriptional activation, while whole cell RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. By integrating the RNA-seq data with ATAC-seq (assay for transposase-accessible chromatin followed by sequencing), we further demonstrated altered chromatin accessibility in key genes associated with these pathways following SUV39H1 knockdown. Treatment with chaetocin, a SUV39H1 inhibitor, mimicked the functional effects of SUV39H1 knockdown in GSCs and sensitized GSCs to the GBM chemotherapy drug temozolomide. Furthermore, targeting SUV39H1 in vivo using a patient-derived xenograft model for GBM inhibited GSC-driven tumor formation. This is the first report demonstrating a critical role for SUV39H1 in GSC maintenance. SUV39H1-mediated targeting of GSCs could enhance the efficacy of existing chemotherapy, presenting a promising strategy for improving GBM treatment and patient outcomes. HighlightsO_LISUV39H1 is upregulated in GBM, especially GSCs C_LIO_LITargeting SUV39H1 disrupts GSC maintenance and sensitizes GSCs to TMZ C_LIO_LITargeting SUV39H1 alters chromatin accessibility at cell cycle and stemness genes C_LIO_LITargeting SUV39H1 suppresses GSC-driven tumors in a patient-derived xenograft model C_LI

cancer biology↗

bioRxiv2023

eQTL mapping in transgenic alpha-synuclein carrying Caenorhabditis elegans recombinant inbred line

Protein aggregation of -synuclein (S) is a genetic and neuropathological hallmark of Parkinsons disease (PD). Studies in the model nematode Caenorhabditis elegans suggested that variation of S aggregation depends on the genetic background. However, which genes and genetic modifiers underlie individual differences in S pathology remains unknown. To study the genotypic-phenotypic relationship of S aggregation, we constructed a Recombinant Inbred Line (RIL) panel derived from a cross between genetically divergent strains C. elegans NL5901 and SCH4856, both harboring the human S gene. As a first step to discover genetic modifiers 70 S-RILs were measured for whole-genome gene expression and expression quantitative locus analysis (eQTL) were mapped. We detected multiple eQTL hot-spots, many of which were located on Chromosome V. To confirm a causal locus, we developed Introgression Lines (ILs) that contain SCH4856 introgressions on Chromosome V in an NL5901 background. We detected 74 genes with an interactive effect between S and the genetic background, including the human p38 MAPK homologue pmk-1 that has previously been associated with PD. Together, we present a unique S-RIL panel for defining effects of natural genetic variation on S pathology, which contributes to finding genetic modifiers of PD.

genomics↗

bioRxiv2022

Two sides to every coin: complementary introgression line populations in Caenorhabditis elegans

Quantitative genetics seeks to understand the role of allelic variation in trait differences. Introgression lines (ILs) contain a single genetic locus introgressed into another genetic background, and are one of the most powerful quantitative trait locus (QTL) mapping designs. However, albeit useful for QTL discovery, this homogenous background confounds genetic interactions. Here, we created an IL population with N2 segments in a CB4856 background (ILCB4856), reciprocal to an N2 background with CB4856 introgressions population (ILN2). The ILCB4856 panel comprises a population of 145 strains with sequencing confirmed N2 introgressions in a CB4856 background. A core set of 87 strains covering the entire genome was selected. We present three experiments demonstrating the power of the reciprocal IL panels. First, we performed QTL mapping identifying new regions associated with lifespan. Second, the existence of opposite-effect loci regulating heat-stress survival is demonstrated. Third, by combining ILN2 and ILCB4856 strains, an interacting expression QTL was uncovered. In conclusion, the reciprocal IL panels are a unique and ready-to-use resource to identify, resolve, and refine complex trait architectures in C. elegans.

genetics↗

bioRxiv2020

The GPIbα intracellular tail - role in transducing VWF- and Collagen/GPVI-mediated signaling

Synergy between GPIb and GPVI signaling machineries has been suggested previously, however its molecular mechanism remains unclear. We generated a novel GPIb transgenic mouse (GPIb{Delta}sig/{Delta}sig) by CRISPR-Cas9 technology to delete the last 24 residues of the GPIb intracellular tail important for VWF-mediated signaling. GPIb{Delta}sig/{Delta}sig platelets bound VWF normally under flow but formed fewer filopodia on VWF/botrocetin, demonstrating that the deleted region does not affect ligand binding but appreciably impairs VWF-dependent signaling. Notably, while haemostasis was normal in GPIb{Delta}sig/{Delta}sig mice, GPIb{Delta}sig/{Delta}sig platelets exhibited defective responses after collagen-related-peptide stimulation and formed smaller aggregates on collagen-coated microchannels at low and high shears. Flow assays performed with plasma-free blood or in the presence of IIb{beta}3-or GPVI-blockers suggested reduced IIb{beta}3 activation contributes to the phenotype of the GPIb{Delta}sig/{Delta}sig platelets. Together, these results reveal a new role for the intracellular tail of GPIb in transducing both VWF-GPIb and collagen-GPVI signaling events in platelets. Summary statementGPIb and GPVI are two key receptors on the platelet surface. Using a novel transgenic mouse (GPIb{Delta}sig/{Delta}sig) that lacks the last 24 amino acids of the GPIb intracellular tail, we demonstrate the importance of this region not only in transducing signals in response to GPIb binding to VWF, but also for collagen-GPVI-mediated platelet responses revealing previously underappreciated receptor crosstalk between GPIb and GPVI.

cell biology↗

bioRxiv2020

Punctuated loci on chromosome IV determine natural variation in Orsay virus susceptibility of Caenorhabditis elegans strains Bristol N2 and Hawaiian CB4856

Host-pathogen interactions play a major role in evolutionary selection and shape natural genetic variation. The genetically distinct Caenorhabditis elegans strains, Bristol N2 and Hawaiian CB4856, are differentially susceptible to the Orsay virus (OrV). Here we report the dissection of the genetic architecture of susceptibility to OrV infection. We compare OrV infection in the relatively resistant wild-type CB4856 strain to the more susceptible canonical N2 strain. To gain insight into the genetic architecture of viral susceptibility, 52 fully sequenced recombinant inbred lines (CB4856 x N2 RILs) were exposed to OrV. This led to the identification of two loci on chromosome IV associated with OrV resistance. To verify the two loci and gain additional insight into the genetic architecture controlling virus infection, introgression lines (ILs) that together cover chromosome IV, were exposed to OrV. Of the 27 ILs used, 17 had an CB4856 introgression in an N2 background and 10 had an N2 introgression in a CB4856 background. Infection of the ILs confirmed and fine-mapped the locus underlying variation in OrV susceptibility and we found that a single nucleotide polymorphism in cul-6 contributes to the difference in OrV susceptibility between N2 and CB4856. An allele swap experiment showed the strain CB4856 became more susceptible by having an N2 cul-6 allele, although having the CB4856 cul-6 allele did not increase resistance in N2. Additionally, we found that multiple strains with non-overlapping introgressions showed a distinct infection phenotype from the parental strain, indicating that there are punctuated locations on chromosome IV determining OrV susceptibility. Thus, our findings reveal the genetic complexity of OrV susceptibility in C. elegans and suggest that viral susceptibility is governed by multiple genes.

genetics↗

bioRxiv2018

C. elegans genetic background modifies the core transcriptional response in an α-synuclein model of Parkinson’s disease

Accumulation of protein aggregates is a major cause of Parkinsons disease (PD), a progressive neurodegenerative condition that is one of the most common causes of dementia. Transgenic Caenorhabditis elegans worms expressing the human synaptic protein -synuclein show inclusions of aggregated protein and replicate the defining pathological hallmarks of PD. It is however not known how PD progression and pathology differs among individual genetic backgrounds. Here, we compared gene expression patterns, and investigated the phenotypic consequences of transgenic -synuclein expression in five different C. elegans genetic backgrounds. Transcriptome analysis indicates that the effects of -synuclein expression on pathways associated with nutrient storage, lipid transportation and ion exchange depend on the genetic background. The gene expression changes we observe suggest that a range of phenotypes will be affected by -synuclein expression. We experimentally confirm this, showing that the transgenic lines generally show delayed development, reduced lifespan, and an increased rate of matricidal hatching. These phenotypic effects coincide with the core changes in gene expression, linking developmental arrest, mobility, metabolic and cellular repair mechanisms to -synuclein expression. Together, our results show both genotype-specific effects and core alterations in global gene expression and in phenotype in response to -synuclein. We conclude that the PD effects are substantially modified by the genetic background, illustrating that genetic background mechanisms should be elucidated to understand individual variation in PD.

genomics↗