Biology subjects

Weng, S.

Publications and source records attributed to Weng, S..

28 records · Page 2Linked to original sources

bioRxiv2022

Gene interaction perturbation network deciphers a high-resolution taxonomy in colorectal cancer

Molecular subtypes of colorectal cancer (CRC) are currently identified via the snapshot transcriptional profiles, largely ignoring the dynamic changes of gene expressions. Conversely, biological networks remain relatively stable irrespective of time and condition. Here, we introduce an individual-specific gene interaction perturbation network-based (GIN) approach and identify six GIN subtypes (GINS1-6) with distinguishing features: (i) GINS1 (proliferative, 24%[~]34%), elevated proliferative activity, high tumor purity, immune-desert, PIK3CA mutations, and immunotherapeutic resistance; (ii) GINS2 (stromal-rich, 14%[~]22%), abundant fibroblasts, immune-suppressed, stem-cell-like, SMAD4 mutations, unfavorable prognosis, high potential of recurrence and metastasis, immunotherapeutic resistance, and sensitive to fluorouracil-based chemotherapy; (iii) GINS3 (KRAS-inactivated, 13%[~]20%), high tumor purity, immune-desert, activation of EGFR and ephrin receptors, chromosomal instability (CIN), fewer KRAS mutations, SMOC1 methylation, immunotherapeutic resistance, and sensitive to cetuximab and bevacizumab; (iv) GINS4 (mixed, 10%[~]19%), moderate level of stromal and immune activities, transit-amplifying-like, and TMEM106A methylation; (v) GINS5 (immune-activated, 12%[~]24%), stronger immune activation, plentiful tumor mutation and neoantigen burden, microsatellite instability and high CpG island methylator phenotype, BRAF mutations, favorable prognosis, and sensitive to immunotherapy and PARP inhibitors; (vi) GINS6, (metabolic, 5%[~]8%), accumulated fatty acids, enterocyte-like, and BMP activity. Overall, the novel high-resolution taxonomy derived from an interactome perspective could facilitate more effective management of CRC patients.

genetics↗

bioRxiv2022

PCP and Septins govern the polarized organization and mechanics of the actin cytoskeleton during convergent extension.

Actin is generally required for cell movement but must be brought under the control of distinct developmental systems to drive specific morphogenetic processes, such as convergent extension (CE)1. This evolutionarily conserved collective cell movement elongates the body axis of all vertebrates and is governed by the Planar Cell Polarity (PCP) signaling system 1,2. Here, we sought to understand the interplay of PCP and actin during Xenopus CE. Our data provide new insights into the organization and emergence of polarity in this network and reveal new roles for the actin organizing Septins 3, thereby shedding light on the mechanisms by which developmental signaling systems exploit the ubiquitous machinery of cells to drive morphogenesis.

developmental biology↗

bioRxiv2022

Comprehensive machine-learning survival framework develop a consensus model in large scale multi-center cohorts for pancreatic cancer

BackgroundAs the most aggressive tumor, the outcome of pancreatic cancer (PACA) has not improved observably over the last decade. Anatomy-based TNM staging does not exactly identify treatment-sensitive patients, and an ideal biomarker is urgently needed for precision medicine. MethodsA total of 1280 patients from 10 multi-center cohorts were enrolled. 10 machine-learning algorithms were transformed into 76 combinations, which were performed to construct an artificial intelligence-derived prognostic signature (AIDPS). The predictive performance, multi-omic alterations, immune landscape, and clinical significance of AIDPS were further explored. ResultsBased on 10 independent cohorts, we screened 32 consensus prognostic genes via univariate Cox regression. According to the criterion with the largest average C-index in the nine validation sets, we selected the optimal algorithm to construct the AIDPS. After incorporating several vital clinicopathological features and 86 published signatures, AIDPS exhibited robust and dramatically superior predictive capability. Moreover, in other prevalent digestive system tumors, the 9-gene AIDPS could still accurately stratify the prognosis. Of note, our AIDPS had important clinical implications for PACA, and patients with low AIDPS owned a dismal prognosis, relatively high frequency of mutations and copy number alterations, and denser immune cell infiltrates as well as were more sensitive to immunotherapy. Correspondingly, the high AIDPS group possessed dramatically prolonged survival, and panobinostat might be a potential agent for patients with high AIDPS. ConclusionsThe AIDPS could accurately predict the prognosis and immunotherapy efficacy of PACA, which might become an attractive tool to further guide the stratified management and individualized treatment. FundingThis study was supported by the National Natural Science Foundation of China (No. 81870457, 82172944).

bioinformatics↗

bioRxiv2021

New Data and Collaborations at the Saccharomyces Genome Database: Updated reference genome, alleles, and the Alliance of Genome Resources

Saccharomyces cerevisiae is used to provide fundamental understanding of eukaryotic genetics, gene product function, and cellular biological processes. Saccharomyces Genome Database (SGD) has been supporting the yeast research community since 1993, serving as its de facto hub. Over the years, SGD has maintained the genetic nomenclature, chromosome maps, and functional annotation, and developed various tools and methods for analysis and curation of a variety of emerging data types. More recently, SGD and six other model organism focused knowledgebases have come together to create the Alliance of Genome Resources to develop sustainable genome information resources that promote and support the use of various model organisms to understand the genetic and genomic bases of human biology and disease. Here we describe recent activities at SGD, including the latest reference genome annotation update, the development of a curation system for mutant alleles, and new pages addressing homology across model organisms as well as the use of yeast to study human disease.

genetics↗

bioRxiv2021

Cell adhesions link subcellular actomyosin dynamics to tissue scale force production during vertebrate convergent extension.

Axis extension is a fundamental biological process that shapes multicellular organisms. The design of an animals body plan is encoded in the genome and execution of this program is a multiscale mechanical progression involving the coordinated movement of proteins, cells, and whole tissues. Thus, a key challenge to understanding axis extension is connecting events that occur across these various length scales. Here, we use approaches from proteomics, cell biology, and tissue biomechanics to describe how a poorly characterized cell adhesion effector, the Armadillo Repeat protein deleted in Velo-Cardio-Facial syndrome (Arvcf) catenin, controls vertebrate head-to-tail axis extension. We find that Arvcf catenin is required for axis extension within the intact organism but is not required for extension of isolated tissues. We then show that the organism scale phenotype is caused by a modest defect in force production at the tissue scale that becomes apparent when the tissue is challenged by external resistance. Finally, we show that the tissue scale force defect results from dampening of the pulsatile recruitment of cell adhesion and cytoskeletal proteins to cell membranes. These results not only provide a comprehensive understanding of Arvcf function during an essential biological process, but also provide insight into how a modest cellular scale defect in cell adhesion results in an organism scale failure of development.

developmental biology↗

bioRxiv2021

Convergent extension requires adhesion-dependent biomechanical integration of cell crawling and junction contraction

Convergent extension is an evolutionarily conserved collective cell movement that elongates the body axis of almost all animals and is required for the morphogenesis of several organ systems. Decades of study have revealed two distinct mechanisms of cell movement during CE, one based on cell crawling and the other on junction contraction. How these two behaviors collaborate during CE is not understood. Here, using quantitative live cell imaging we show that these two modes act both independently and in concert during CE, but that cell movement is more effective when the two modes are integrated via mechano-reciprocity. Based on these findings, we developed a novel computational model that for the first time treats crawling and contraction independently. This model not only confirmed the biomechanical efficacy of integrating the two modes, but also revealed for the first time how the two modes -and their integration- are influenced by cell adhesion. Finally, we use these new insights to further understand the complex CE phenotype resulting from loss of the C-cadherin interacting catenin Arvcf. These data are significant for providing new biomechanical and cell biological insights into a fundamental morphogenetic process that is implicated in human neural tube defects and skeletal dysplasias.

developmental biology↗

bioRxiv2020

Cadherin clustering controls heterogeneous, asymmetric junction dynamics during vertebrate axis elongation

Morphogenesis is governed by the interplay of molecular signals and mechanical forces across multiple length scales. The last decade has seen tremendous advances in our understanding of the dynamics of protein localization and turnover at sub-cellular length scales, and at the other end of the spectrum, of mechanics at tissue-level length scales. Integrating the two remains a challenge, however, because we lack a detailed understanding of the subcellular patterns of mechanical properties of cells within tissues. Here, in the context of the elongating body axis of a vertebrate embryo, we combine tools from cell biology and physics to demonstrate that individual cell-cell junctions display finely-patterned local mechanical heterogeneity along their length. We show that such local mechanical patterning is essential for the cell movements of convergent extension and is imparted by locally patterned clustering of a classical cadherin. Finally, the patterning of cadherins and thus local mechanics along cell-cell junctions are controlled by Planar Cell Polarity signaling, a key genetic module for CE that is mutated in diverse human birth defects.

cell biology↗

bioRxiv2019

ConnectedReads: machine-learning optimized long-range genome analysis workflow for next-generation sequencing

Current human genome sequencing assays in both clinical and research settings primarily utilize short-read sequencing and apply resequencing pipelines to detect genetic variants. However, theses mapping-based data analysis pipelines remains a considerable challenge due to an incomplete reference genome, mapping errors and high sequence divergence. To overcome this challenge, we propose an efficient and effective whole-read assembly workflow with unsupervised graph mining algorithms on an Apache Spark large-scale data processing platform called ConnectedReads. By fully utilizing short-read data information, ConnectedReads is able to generate assembled contigs and then benefit downstream pipelines to provide higher-resolution SV discovery than that provided by other methods, especially in high diversity against reference and N-gap regions of reference. Furthermore, we demonstrate a cost-effective approach by leveraging ConnectedReads to investigate all spectra of genetic changes in population-scale studies.

bioinformatics↗

bioRxiv2018

Microbial Cells Harboring a Mitochondrial Gene Are Capable of CO2 Capture

Global warming is escalating with increased temperatures reported worldwide. Given the enormous land mass on the planet, biological capture of CO2 remains a viable approach to mitigate the crisis as it is economical and easy to implement. In this study, a gene capable of CO2 capture was identified via selection in minimal media. This mitochondrial gene named as OG1 encodes the OK/SW-CL.16 protein and shares homology with cytochrome oxidase subunit III of various species and PII uridylyl-transferase from Loktanella vestfoldensis SKA53. CO2 capture experiments indicate that {delta}13C was substantially higher in the cells harboring the gene OG1 than the control in the nutrition-poor media. This study suggests that CO2 capture using engineered microorganisms in barren land can be exploited to address the soaring CO2 level in the atmosphere, opening up vast land resources to cope with global warming.\n\nIMPORTANCEGlobal warming crisis is deteriorating with increased CO2 levels in the atmosphere each year. Action must be taken before catastrophic consequences occur in the not-so-distant future. Biological capture of CO2 is a feasible approach to alleviate the current crisis. We have identified a mitochondrial gene which demonstrated CO2 utilization capability. Data presented in this study suggest that CO2 capture using engineered microorganisms can be harnessed to address the ever-rising CO2 level in the atmosphere.

bioengineering↗

bioRxiv2018

UBE2G1 Governs the Destruction of Cereblon Neomorphic Substrates

The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide as well as the novel cereblon modulating agents (CMs) including CC-122, CC-220 and cereblon-based proteolysis-targeting chimaeras (PROTACs) repurpose the Cul4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase complex to induce the degradation of specific neomorphic substrates via polyubiquitination in conjunction with an E1 ubiquitin-activating enzyme and E2 ubiquitin-conjugating enzymes, which have until now remained elusive. Here we show that the ubiquitin-conjugating enzymes UBE2G1 and UBE2D3 cooperatively promote the polyubiquitination of CRL4CRBN neomorphic substrates in a cereblon- and CM-dependent manner via a sequential ubiquitination mechanism: UBE2D3 transforms the neomorphic substrates into mono-ubiquitinated forms, upon which UBE2G1 catalyzes K48-linked polyubiquitin chain extension. Blockade of UBE2G1 diminishes the ubiquitination and degradation of neomorphic substrates, and consequent antitumor activities elicited by all tested CMs. For example, UBE2G1 inactivation significantly attenuated the degradation of myeloma survival factors IKZF1 and IKZF3 induced by lenalidomide and pomalidomide, hence conferring drug resistance. UBE2G1-deficient myeloma cells, however, remained sensitive to a more potent IKZF1/3 degrader CC-220. Collectively, these findings suggest that loss of UBE2G1 activity might be a resistance mechanism to drugs that hijack the CRL4CRBN to eliminate disease-driving proteins, and that this resistance mechanism can be overcome by next-generation CMs that destroy the same targeted protein more effectively.

molecular biology↗