Biology subjects

Dai, Z.

Publications and source records attributed to Dai, Z..

5 recordsLinked to original sources

bioRxiv2018

Genetically modified pigs are protected from classical swine fever virus

Classical swine fever (CSF) caused by classical swine fever virus (CSFV) is among the most detrimental diseases, and leads to significant economic losses in the swine industry. Despite efforts by many government authorities try to stamp out the disease from national pig populations, the disease remains widespread. Here, antiviral small hairpin RNAs (shRNAs) were selected and then inserted at the porcine ROSA26 (pROSA26) locus via a CRISPR/Cas9-mediated knock-in strategy. Finally, anti-CSFV transgenic (TG) pigs were produced by somatic nuclear transfer (SCNT). Importantly, in vitro and in vivo viral challenge assays demonstrated that these TG pigs could effectively limit the growth of CSFV and reduced CSFV-associated clinical signs and mortality, and the disease resistance was stably transmitted to F1-generation. The use of these TG pigs can improve the well-being of livestock and substantially reduce virus-related economic losses. Additionally, this antiviral approach may provide a reference for future antiviral research.\n\nAuthor summaryClassical swine fever (CSF), caused by classical swine fever virus (CSFV), and is a highly contagious, often fatal porcine disease with significant economic losses. Due to its economic importance to the pig industry, the biology and pathogenesis of CSFV have been investigated extensively. Despite efforts by many government authorities to stamp out the disease from national pig populations, the disease remains widespread in some regions and seems to be waiting for the reintroduction and the next round of disease outbreaks. These highlight the necessity and urgency of developing more effective approaches to eradicate the challenging CSFV. In this study, we successfully produced anti-CSFV transgenic pigs and confirmed that these transgenic pigs could effectively limit the growth of CSFV in vivo and in vitro and that the disease resistance traits in the TG founders can be stably transmitted to their F1-generation offspring. This study suggests that these TG pigs can improve the well-being of livestock and contribute to offer potential benefits over commercial vaccination. The use of these TG pigs can improve the well-being of livestock and substantially reduce CSFV-related economic losses.

genomics↗

bioRxiv2018

Thermodynamic constraints on the regulation of metabolic fluxes

Nutrition and metabolism are fundamental to cellular function in physiological and pathological contexts. Metabolic activity (i.e. rates, flow, or most commonly referred to as flux) is constrained by thermodynamics and regulated by the activity of enzymes. The general principles that relate biological and physical variables to metabolic control are incompletely understood. Using metabolic control analysis in several representative topological structures of metabolic pathways as models, we derive exact results and conduct computer simulations that define relationships between thermodynamics, enzyme activity, and flux control. We confirm that metabolic pathways that are very far from equilibrium are controlled by the activity of upstream enzymes. However, in general, metabolic pathways have a more adaptable pattern of regulation, controlled minimally by thermodynamics and not necessarily by the specific enzyme that generates the given reaction. These findings show how the control of metabolic pathways, which are rarely very far from equilibrium, is largely set by the overall flux through a pathway rather than by the enzyme which generates the flux or by thermodynamics.

biophysics↗

bioRxiv2018

Environmental factors shape methionine metabolism in p16/MTAP deleted cells

The co-deletion of a common tumor suppressor locus and neighboring metabolic gene is an attractive possible synthetic dependency of tumor suppression on metabolism. However, the general impact that these co-deletions have on metabolism, which also dependent on nutrient availability and the tissue of origin, is unknown. As a model to investigate this question, we considered a set of tissue-matched cancer cells with homozygous co-deletions in CDKN2a and MTAP, genes respectively encoding the most commonly deleted tumor suppressor p16 and an enzyme involved in methionine metabolism. A comparative metabolomics analysis revealed that while there exists a definite pan-cancer metabolic signature of MTAP-deletion, this signature was not preserved when cells were subjected to changes in the availability of methionine, serine, or cysteine, nutrients related to methionine metabolism. Notably, the heterogeneity exhibited by these cells in their responsiveness to nutrient availability dominated both MTAP status and tissue-of-origin. Furthermore, re-expression of MTAP exerted a modest effect on metabolism. Together these findings demonstrate that environmental factors, particularly nutrition and tissue identity, may overwhelm the genetic effects of collateral deletions of metabolic genes.

molecular biology↗

bioRxiv2018

Methionine metabolism influences the genomic architecture of H3K4me3 with the link to gene expression encoded in peak width

Nutrition and metabolism are known to influence chromatin biology and epigenetics by modifying the levels of post-translational modifications on histones, yet how changes in nutrient availability influence specific aspects of genomic architecture and connect to gene expression is unknown. To investigate this question we considered, as a model, the metabolically-driven dynamics of H3K4me3, a histone methylation mark that is known to encode information about active transcription, cell identity, and tumor suppression. We analyzed the genome-wide changes in H3K4me3 and gene expression in response to alterations in methionine availability under conditions that are known to affect the global levels of histone methylation in both normal rodent physiology and in human cancer cells. Surprisingly, we found that the location of H3K4me3 peaks at specific genomic loci was largely preserved under conditions of methionine restriction. However, upon examining different geometrical features of peak shape, it was found that the response of H3K4me3 peak width encoded almost all aspects of H3K4me3 biology including changes in expression levels, and the presence of cell identity and cancer associated genes. These findings reveal simple yet new and profound principles for how nutrient availability modulates specific aspects of chromatin dynamics to mediate key biological features.

genetics↗

bioRxiv2017

Identification of Cancer-associated Metabolic Vulnerabilities by Modeling Multi-objective Optimality in Metabolism

Computational modeling of the genome-wide metabolic network is essential for designing new therapeutics targeting cancer-associated metabolic disorder, which is a hallmark of human malignancies. However, previous studies generally assumed that metabolic fluxes of cancer cells are subjected to the maximization of biomass production, despite the wide existence of trade-offs among multiple metabolic objectives. To address this issue, we developed a multi-objective model of cancer metabolism with algorithms depicting approximate Pareto surfaces and incorporating multiple omics datasets. To validate this approach, we built individualized models for NCI-60 cancer cell lines, and accurately predicted cell growth rates and other biological consequences of metabolic perturbations in these cells. By analyzing the landscape of approximate Pareto surface, we identified a list of metabolic targets essential for cancer cell proliferation and the Warburg effect, and further demonstrated their close association with cancer patient survival. Finally, metabolic targets predicted to be essential for tumor progression were validated by cell-based experiments, confirming this multi-objective modelling method as a novel and effective strategy to identify cancer-associated metabolic vulnerabilities.

systems biology↗