Biology subjects

Pu, W.

Publications and source records attributed to Pu, W..

11 recordsLinked to original sources

bioRxiv2026

Evolutionary and multi-omic divergences associated with the extreme sexual size dimorphism in spiders

Extreme sexual size dimorphism (SSD) represents one of the most striking forms of phenotypic divergence between the sexes, yet the genomic basis of extreme body-size dimorphism remains poorly understood. Orb-weaving spiders exhibit some of the most pronounced female-biased SSD among terrestrial arthropods, providing an exceptional system for investigating the evolutionary and genomic changes associated with extreme SSD. Here, we combined comparative genomics across 51 spider species with sex-resolved transcriptomic and chromatin profiling in the highly dimorphic Joro spider, Trichonephila clavata. Across spiders, we identified SSD-associated evolutionary-rate shifts in genes involved in chromatin regulation, growth, and cuticle structural organization. We further found a significant positive association between JHAMT copy number and SSD, with larger gene repertoires occurring in more extremely dimorphic lineages. In T. clavata, expanded JHAMT paralogs showed sex- and tissue-biased expression together with sex-specific differences in chromatin accessibility and local chromatin interactions. Integrated multi-omic analyses further revealed coordinated sex-specific differences in transcription, chromatin accessibility, and chromatin interactions across genes involved in ecdysteroid signaling, insulin and growth regulation, and epidermal and cuticular processes. Altogether, these findings provide insight into the evolutionary and regulatory changes associated with extreme female-biased SSD in spiders.

zoology↗

bioRxiv2025

Genomic signatures associated with convergent funnel-web building behavior in spiders

Spiders exhibited diverse and intricate web-building behaviors, which represent a classic model for studying the evolution of complex traits. The funnel-web, a sheet-like web with a retreat tube, has evolved independently in several spider lineages, especially in the families Agelenidae and Macrothelidae. This repeated emergence of a complex behavior offers an example of this funnel-web building behavioral convergence. Here, we present a chromosome-level genome assembly of the agelenid spider Tamgrinia laticeps, along with annotated genomes of another agelenid spider Eratigena atrica, and a macrothelid Orientothele yani which convergently evolved funnel-web building behavior. Comparative genomic analysis of 15 spider species with diverse web-types revealed convergent signatures associated with funnel-web construction. Hundreds of genes tended to experience convergent shift in selective pressure, convergent positive section, and harbored convergent amino acid substitutions. These genes are associated with synaptic transmission (e.g., SLC6A3, Gabbr1, SNAP25), neuromuscular coordination (e.g., ine, VAChT), and behavioral regulation (e.g., Crtc1, Lrrc7). Notably, we detected identical convergent amino acid changes in VAChT and ine across all three funnel-web builders. Our findings demonstrate that convergent evolution of web architecture is linked to nervous system evolution, providing genomic insights into the basis of behavioral convergence.

genomics↗

bioRxiv2024

The robust, high-throughput, and temporally regulated roxCre and loxCre reporting systems for genetic modifications in vivo

Cre-loxP technology, a cornerstone in fate mapping and in vivo gene function studies, faces challenges in achieving precise and efficient conditional mutagenesis through inducible systems. This study introduces two innovative genetic tools designed to overcome these limitations. The first, roxCre, enables DreER-mediated Cre release, paving the way for intersectional genetic manipulation that permits increased precision and efficiency. The second, loxCre, facilitates conditional gene targeting by allowing CreER lines to induce Cre expression with significantly enhanced efficiency. These tools incorporate a fluorescent reporter for genetic lineage tracing, simultaneously revealing efficient gene knockout in cells marked by the reporter. These strategies hold great potential for precise and efficient exploration of lineage-specific gene functions, marking a significant advancement in genetic research methodologies.

genetics↗

bioRxiv2023

Non-cell autonomous cardiomyocyte regulation complicates gene supplementation therapy for LMNA cardiomyopathy

AimsRecombinant adeno-associated viruses (rAAVs) are federally approved gene delivery vectors for in vivo gene supplementation therapy. Loss-of-function truncating variants of LMNA, the coding gene for Lamin-A/C, are one of the primary causes of inherited dilate cardiomyopathy (DCM). Here we aim to study whether AAV-based LMNA supplementation could treat LMNA deficiency-triggered cardiac defects. Methods and ResultsWe compared whole-body, cardiomyocyte-specific and genetic-mosaic mouse models that carry Lmna truncating variants at the same genetic loci and uncovered primarily a non-cell autonomous impact of Lmna on cardiomyocyte maturation. Whole-body lamin-A supplementation by rAAVs moderately rescued the cardiac defects in Lmna germline mutants. By contrast, cardiomyocyte-specific lamin-A addback failed to restore the cardiomyocyte growth defects. A Cre-loxP-based AAV vector that expresses lamin-A throughout the body but excluding the heart was able to restore cardiomyocyte growth in Lmna germline mutants. ConclusionsLmna regulates cardiomyocyte growth non-cell autonomously. Non-myocytes are the key cell targets for a successful gene therapy for LMNA-associated cardiac defects. Translational perspectiveLMNA truncating mutations are among the major causes of inherited DCM. AAV gene supplementation therapy is emerging as a promising strategy to treat genetic cardiomyopathy, but whether this strategy is suitable for LMNA cardiomyopathy remained unclear. Our study counterintuitively showed that the cardiomyocytes are not necessarily the correct therapeutic cell targets for AAV-based treatment of LMNA cardiomyopathy. By contrast, careful elucidation of cell-autonomous versus non-cell-autonomous gene functions is essential for the proper design of a gene supplementation therapy for cardiomyopathy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/549413v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@37cfdaorg.highwire.dtl.DTLVardef@2f2cd1org.highwire.dtl.DTLVardef@1278d08org.highwire.dtl.DTLVardef@19c4869_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Airway secretory cell-derived p63+ progenitors contribute to alveolar regeneration after sterile lung injury

Lung injury activates epithelial stem or progenitor cells for alveolar repair and regeneration. However, the origin and fate of injury-induced progenitors are poorly defined. Here, we report that p63-expressing progenitors emerge upon bleomycin-induced lung injury. These p63+ progenitors proliferate rapidly and differentiate into alveolar type 1 (AT1) and type 2 (AT2) cells through distinct trajectories. Dual recombinase-mediated sequential genetic lineage tracing reveals that p63+ progenitors originate from airway secretory cells and subsequently generate alveolar cells. Functionally, p63 activation is required for efficient alveolar regeneration from secretory cells. Our study identifies a secretory cell-derived p63+ progenitor that contributes to alveolar repair, indicating a potential therapeutic avenue for lung regeneration after injury.

cell biology↗

bioRxiv2021

Inhibition of HSP90 reversed STAT3 mediated muscle wasting induced by cancer cachexia

Cancer cachexia is one of the most common causes of death among cancer patients, no effective anti-cachectic treatment is currently available. In experimental cachectic models, aberrant activation of STAT3 in skeletal muscle has been found to contribute to muscle wasting. However, its clinical association, the factors regulating STAT3 activation, and the molecular mechanisms of STAT3-induced muscle atrophy in cancer cachexia remain incompletely understood. Here, we show that an enhanced interaction between STAT3 and HSP90, which causes the persistent STAT3 activation in the skeletal muscle of cancer cachexia patients, is the crucial event for the development of cachectic muscle wasting. Administration of HSP90 inhibitors alleviated the muscle wasting in C26 tumor-bearing cachetic mice model or C26 conditional medium induced C2C12 myotube atrophy. A mechanistic study indicated that in cachectic skeletal muscle, prolonged STAT3 activation triggered muscle wasting in a FOXO1-dependent manner, STAT3 activated FOXO1 by binding directly to its promoter. Our results provide key insights into the role of the HSP90/STAT3/FOXO1 axis in cachectic muscle wasting, which shows promising therapeutic potential as a target for the treatment of cancer cachexia.

pathology↗

bioRxiv2020

Robust differentiation of human pluripotent stem cells into endothelial cells via temporal modulation of ETV2 with modified mRNA

Human induced pluripotent stem cell (h-iPSC)-derived endothelial cells (h-iECs) have become a valuable tool in regenerative medicine. However, current differentiation protocols remain inefficient and lack reliability. Here, we describe a method for rapid, consistent, and highly efficient generation of h-iECs. The protocol entails the delivery of modified mRNA encoding the transcription factor ETV2 at the intermediate mesodermal stage of differentiation. This approach reproducibly differentiated thirteen diverse h-iPSC lines into h-iECs with exceedingly high efficiency. In contrast, standard differentiation methods that relied on endogenous ETV2 were inefficient and notably inconsistent. Our h-iECs were functionally competent in many respects, including the ability to form perfused vascular networks in vivo. Importantly, timely activation of ETV2 was critical, and bypassing the mesodermal stage produced putative h-iECs with reduced expansion potential and inability to form functional vessels. Our protocol has broad applications and could reliably provide an unlimited number of h-iECs for vascular therapies.

cell biology↗

bioRxiv2020

Altered Temporal Variability of Local and Large-scale Resting-state Brain Functional Connectivity Patterns in Schizophrenia and Bipolar Disorder

Schizophrenia and bipolar disorder share some common clinical features and are both characterized by aberrant resting-state functional connectivity (FC). However, little is known about the common and specific aberrant features of the dynamic FC patterns in these two disorders. In this study, we explored the differences in dynamic FC among schizophrenia patients (n = 66), type I bipolar disorder patients (n = 53) and healthy controls (n = 66), by comparing temporal variabilities of FC patterns involved in specific brain regions and large-scale brain networks. Compared with healthy controls, both patient groups showed significantly increased regional FC variabilities in subcortical areas including the thalamus and basal ganglia, as well as increased inter-network FC variability between the thalamus and sensorimotor areas. Specifically, more widespread changes were found in the schizophrenia group, involving increased FC variabilities in sensorimotor, visual, attention, limbic and subcortical areas at both regional and network levels, as well as decreased regional FC variabilities in the default-mode areas. The observed alterations shared by schizophrenia and bipolar disorder may help to explain their overlapped clinical features; meanwhile, the schizophrenia-specific abnormalities in a wider range may support that schizophrenia is associated with more severe functional brain deficits than bipolar disorder.

neuroscience↗

bioRxiv2019

Sarcomeres regulate cardiomyocyte maturation through MRTF-SRF signaling

Cardiomyocyte maturation is essential for robust heart contraction throughout life. The signaling networks governing cardiomyocyte maturation remain poorly defined. Our prior studies established the transcription factor SRF as a key regulator of the assembly of sarcomeres, the contractile unit of cardiomyocytes. Whether sarcomeres regulate other aspects of maturation remains unclear. Here we generated mice with cardiomyocyte specific, mosaic mutation of -actinin-2 (Actn2), a key organizer of sarcomeres, to study its cell-autonomous role in cardiomyocyte maturation. In addition to the expected structural defects, Actn2 mutation triggered dramatic transcriptional dysregulation, which strongly correlated with transcriptional changes observed in SRF-depleted cardiomyocytes. Actn2 mutation increased monomeric actin, which perturbed the nuclear localization of the SRF cofactor MRTFA. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the transcriptional and morphological defects in Actn2 and Srf mutant cardiomyocytes. Together, we demonstrate that ACTN2-based sarcomere assembly and MRTF-SRF signaling establish a positive feedback loop that promotes cardiomyocyte maturation.

developmental biology↗

bioRxiv2018

Evaluation of the antifibrotic potency by knocking down SPARC, CCR2 and SMAD3

The genes of SPARC, CCR2, and SMAD3 are implicated in orchestrating inflammation and fibrosis in scleroderma and other fibrotic disorders. Aim of the studies was to examine synergistic effect of inhibition of these genes in treating fibrosis. The peptide nanoparticles were used to deliver the siRNAs in bleomycin-induced fibrotic mice. Triple combination of siRNAs targeting on Sparc, Ccr2 and Smad3 achieved favorable anti-inflammatory and anti-fibrotic effects. Inhibition of inflammation was evidenced by reduced inflammatory cells and proinflammatory cytokines in the BALF and/or the tissues. Activation of fibroblasts was suppressed in mouse tissues in which -Sma and collagens were significantly reduced. Aberrant expression of the genes in fibroblasts, monocytes/macrophage, endothelial and epithelial cells were reinstalled after the treatment. In addition, transcriptome profiles indicated that some bleomycin-induced alterations of multiple biological pathways were recovered to varying degrees by the treatment. The results indicated that the triple combination of siRNAs systemically reinstated multiple biopathways, probably through controlling on different cell types including fibroblasts, monocytes/macrophages, endothelial cells and others. The multi-target-combined therapeutic approach examined herein may represent a novel and effective therapy for fibrosis.

molecular biology↗

bioRxiv2018

Using composite phenotypes to reveal heterogeneity and model SpO2 of altitude acclimatization

Altitude acclimatization is the physiological process of the human body adjusting to the decreased availability of oxygen. Since several physiological processes are involved and the relation among them is complicated, analyses of single-traits is insufficient in revealing the complex mechanism of altitude acclimatization. In this study, we examined whether these physiological responses could be studied as composite phenotypes which are represented by a linear combination of physiological traits. We developed a strategy which combines both spectral clustering and PLSPM to define composite phenotypes. We captured 14 composite phenotypes from 28 physiological traits of altitude acclimatization. Using these composite phenotypes, we applied k-means to reveal hidden physiological heterogeneity in altitude acclimatization. Furthermore, we employed linear regression to systematically model oxygen saturation (SpO2) changes in altitude acclimatization and evaluated the model fitness performance. And composite phenotypes based Model 2 has better fitness than single-traits based Model 1 in all measurement indices. Therefore, this new strategy of defining and applying composite phenotypes can be considered as a general strategy of complex traits.

systems biology↗