Biology subjects

Zhang, X.-S.

Publications and source records attributed to Zhang, X.-S..

10 recordsLinked to original sources

bioRxiv2026

Critical assessment of intratumor and low-biomass microbiome using long-read sequencing

The detection of low-biomass microbial DNA in human tissues is often confounded by contamination, as demonstrated in the debates over the existence of microbiomes in the placenta, brain, blood, and tumors. Here we show that genomic DNA fragment length serves as a discriminator: while genuine microbiome genomes have long genomic DNA fragments, contaminant DNA is typically short. Using germ-free mouse tissues with bacterial spike-ins and human cell lines, we developed a metric that normalizes microbial read length to host read length. Across multiple human tumor and normal tissues, we found genuine microbiome signals are largely limited to tissues with natural microbial exposure (e.g., gastrointestinal tract, cervix, vagina, skin), while other tissues (e.g. kidney, brain, blood, and placenta) showed no evidence of resident microbiome. These findings support DNA fragment length as a metric for quality controlling low-biomass microbiome profiling, clarifying the debates and strengthen future studies of resident microbiome in tissues.

genomics↗

bioRxiv2025

The 16p11.2 microdeletion influences how early-life microbiota perturbations affect hippocampal development and behavior throughout the lifespan

Neurodevelopmental disorders (NDDs) arise from interactions between genetic factors and environmental exposures, with infancy representing a critical period of vulnerability. This exploratory, preclinical study investigated whether the 16p11.2 microdeletion (16pDel), a NDD-associated genetic variant, exacerbates the effects of early-life therapeutic antibiotic exposure on the gut microbiome, hippocampal development, and behavior. Cefdinir, selected for its epidemiological association with NDD risk, acutely perturbed the gut microbiome, causing sustained reductions in Lachnospiraceae. These changes were followed by alterations in sociability, risk assessment, and associative learning. Notably, only cefdinir-exposed 16pDel mice exhibited altered hippocampal stem cell dynamics and gene expression, demonstrating genotype-dependent susceptibility. Increased intestinal permeability and alterations in arginine biosynthesis and glycerophospholipid metabolism implicate gut barrier dysfunction as a contributing factor. Our findings suggest that genetic composition can exacerbate neurodevelopmental consequences of early-life microbiome perturbations, identify metabolic pathways for potential interventions, and support cautious antibiotic use during infancy, especially in genetically vulnerable populations.

neuroscience↗

bioRxiv2025

Gut microbiota phospholipids regulate intestinal gene expression and can counteract the effects of antibiotic treatment

The gut microbiome influences immune and metabolic homeostasis. Our research using non-obese diabetic (NOD) mice revealed that early-life antibiotic exposure remodels the gut microbiome affecting metabolism and accelerating type 1 diabetes (T1D) incidence, with cecal material transplant (CMT) mitigating the damage. Now examining murine intestinal lipidomic profiles, we identified 747 compounds. Comparing the lipidomic profiles of cecal contents of conventional and germ-free mice and their diets, we identified 87 microbially-produced lipids reduced by antibiotic exposure but CMT-restored. Parallel analysis of human fecal lipid profiles after azithromycin-exposure showed significant alterations with substantial overlap with mice. In vitro co-culture with mouse macrophages or small intestinal epithelial cells and human colonic epithelial cells identified phospholipids that repress inflammation through the NF{kappa}B pathway. Oral administration of these phospholipids to antibiotic-treated NOD mice reduced expression of ileal genes involved in early stages of T1D pathogenesis. These findings indicate potential therapeutic anti-inflammatory roles of microbially-produced lipids.

microbiology↗

bioRxiv2025

Epigenetic phase variation in the gut microbiome enhances bacterial adaptation

The human gut microbiome within the gastrointestinal tract continuously adapts to variations in diet, medications, and host physiology. A strategy for bacterial genetic adaptation is epigenetic phase variation (ePV) mediated by bacterial DNA methylation, which can regulate gene expression, enhance clonal heterogeneity, and enable a single bacterial strain to exhibit variable phenotypic states. Genome-wide and site-specific ePVs have been characterized in human pathogens antigenic variation and virulence factor production. However, the role of ePV in facilitating adaptation within the human microbiome remains poorly understood. Here, we comprehensively cataloged genome-wide and site-specific ePV in human infant and adult gut microbiomes. First, using long-read metagenomic sequencing, we detected genome-wide ePV mediated by complex structural variations of DNA methyltransferases, highlighting those associated with antibiotics or fecal microbiota transplantation. Second, we analyzed a collection of public short-read metagenomic sequencing datasets, uncovering a great prevalence of genome-wide ePV in the human gut microbiome. Third, we quantitatively detected site-specific ePVs using single-molecule methylation analysis to identify dynamic variation associated with antibiotic treatment or probiotic engraftment. Finally, we performed an in-depth assessment of an Akkermansia muciniphila isolate from an infant, highlighting that ePVs can regulate gene expression and enhance the bacterial adaptive capacity by employing a bet-hedging strategy to increase tolerance to differing antibiotics. Our findings indicate that epigenetic modifications are a common strategy used by gut bacteria to adapt to the fluctuating environment.

microbiology↗

bioRxiv2024

Critical assessment of nanopore sequencing for the detection of multiple forms of DNA modifications

While nanopore sequencing is increasingly used for mapping DNA modifications, it is important to recognize associated false-positive calls, as they can mislead biological interpretations. To assist biologists and methods developers, we describe a framework, modFDR, for rigorous evaluation that emphasizes the use of the false discovery rate with rationally designed negative controls capturing both general background and confounding modifications. Our critical assessment across multiple DNA modifications shows that while nanopore sequencing performs reliably for high-abundance modifications--including 5-methylcytosine (5mC) at CpG sites in mammalian cells and 5-hydroxymethylcytosine (5hmC) in mammalian brain cells--it produces a substantial fraction of false-positive detections for low-abundance modifications, such as 5mC at CpH sites, 5hmC, and N6-methyldeoxyadenine (6mA) in most mammalian cell types. Although newer models improve certain aspects, systematic false positives remain, and we further observe elevated false negatives for 5mCpG when benchmarked against orthogonal enzymatic methods. This study highlights the urgent need to incorporate modFDR into future methods development, evaluation, and biological studies, and advocates prioritizing nanopore sequencing for mapping abundant rather than rare modifications in biomedical applications.

genomics↗

bioRxiv2022

mEnrich-seq: Methylation-guided enrichment sequencing of bacterial taxa of interest from microbiome

Metagenomics has enabled the comprehensive study of microbiomes. However, many applications would benefit from a method that can sequence specific bacterial taxa of interest (pathogens, beneficial microbes, or low-abundance taxa), but not the vast background of other taxa in a microbiome sample. To address this need, we developed mEnrich-seq, a method that can enrich taxa of interest from metagenomic DNA before sequencing. The core idea is to exploit the self vs. non-self genome differentiation provided by natural bacterial DNA methylation and rationally choose methylation-sensitive restriction enzymes (REs), individually or in combination, to deplete host DNA and most background microbial DNA while enriching bacterial taxa of interest. This core idea is integrated with library preparation procedures in a way that only non-digested DNA libraries are sequenced. We performed in-depth evaluations of mEnrich-seq and demonstrated its use in several applications to enrich (up to 117-fold) genomic DNA of pathogenic or beneficial bacteria from human urine and fecal samples, including several species that are hard to culture or of low abundance. We also assessed the broad applicability of mEnrich-seq and found that 3130 (68.03%) of the 4601 strains with mapped methylomes to date can be targeted by at least one commercially available RE, representing 54.78% of the species examined in this analysis. mEnrich-seq provides microbiome researchers with a versatile and cost-effective approach for selective sequencing of diverse taxa of interest directly from the microbiome.

genomics↗

bioRxiv2021

Phylogeography of the desert scorpion Mesobuthus mongolicus illuminates a route out of Central Asia and Junggar Basin as a corridor for faunal exchange between Central and East Asia

A comprehensive understanding of the ecological, evolutionary and genetic consequences of climate changes requires integration of information from different geographic regions and ecosystems. However, a clear knowledge gap exists in arid biota of Asian drylands, where climate change and biological evolution demonstrate high regional specificity. We report here our phylogeographic study on the desert scorpion Mesobuthus mongolicus, attempting to narrow the gap. Range wide samples for one mitochondrial gene and three nuclear loci were subjected to phylogenetic inferences, molecular dating, Bayesian phylogeographic and demographic reconstructions, and population genetic analyses. Ecological niche modeling was employed to generate models of potential distribution range at present and during the last glacial maximum (LGM). Our results revealed that M. mongolicus represents a single coherent lineage that diverged with its most closely related lineage from Central Asia about 1.36 Ma and underwent radiation ever since. Bayesian phylogeographic reconstruction suggested the ancestral population of M. mongolicus dispersed gradually eastward through the Junngar Basin to the Gobi region during the late Pleistocene, strengthening the view that the Junggar Basin has constituted an important corridor for faunal exchange between Central Asian and East Asia. We found that the desert scorpion underwent demographic expansion while experiencing range contraction during the LGM. Development of sandy deserts in northwest China incurred by Eurasian aridification might have opened up substantial empty niches that sustained population expansion during the LGM. Our results suggested that organisms ecological adaptations have acted as an important determinant for their phylogeographic and demographic responses to past climate changes.

evolutionary biology↗

bioRxiv2019

Genetic analysis and ecological niche modeling delimit species boundary of the Przewalski’s scorpion (Scorpiones: Buthidae) in arid Asian inland

Reliable delimitation of venomous scorpions is not only consequential to toxicological studies but also instructive to conservation and exploration of these important medical resources. In the present study, we delimited species boundary for the the Przewalski’s scorpion from arid northwest China through a combined approach employing phylogenetic analysis, ecological niche modeling and morphological comparison. Our results indicate that the the Przewalski’s scorpion represent an independent taxonomic unit and should be recognized as full species rank, Mesobuthus przewalsii stat. n.. This species and the Chinese scorpion M. martensii represent the eastern members of the M. caucasicus species group which manifests a trans-Central Asia distribution across the Tianshan Mountains range. We also discussed the likely geographic barrier and climatic boundary that demarcate distributional range of the the Przewalski’s scorpion.Competing Interest StatementThe authors have declared no competing interest.View Full Text

zoology↗

bioRxiv2018

Positively interacting strains that circulate in a network structured population induce cycling epidemics of Mycoplasma Pneumoniae

In many countries Mycoplasma pneumoniae (MP) epidemics last approximately one to two years and occur every three to seven years. Poor understanding of the drivers of recurrent MP epidemics limits the predictability of and dynamic responses to the outbreak. Taking into account network structured contacts among people and co-circulating strains of MP, we propose a multi-strain SIRS network model of epidemics of MP where different strains interact during re-infection and within secondary infection. Simulations show that although strain interactions and network-mediated spatial correlations are two separate mechanisms for MP epidemics cycling, each requires very restricted model parameter values such as strong strain interactions and strong network contacts, respectively. When both mechanisms work collectively, MP recurrent epidemics become feasible within the plausible ranges of model parameters. This indicates that positively interacting strains that co-circulate within network contacts induce periodicity and dominant strain shift in observed MP incidence.

epidemiology↗

bioRxiv2018

Acidic microenvironment shaped by lactate accumulation promotes pluripotency through multiple mechanisms

Enhanced glycolysis is a distinct feature associated with numerous stem cells and cancer cells. However, little is known about its regulatory roles in gene expression and cell fate determination. Here we show that acidic environment shaped by lactate accumulation promotes the self-renewal and pluripotency of both mouse and human embryonic stem cells (ESCs). Mechanistically, acidic pH reduces the tri-methylation of H3K27 globally at transcriptional start sites to partially prevent ESC differentiation. In addition, acidic pH stabilizes a large number of mRNAs including pluripotency genes. Furthermore, we found that AGO1 protein is downregulated at acidic conditions, leading to the de-repression of a subset of microRNA targets in low-pH treated ESCs. Altogether, our study provides insights into mechanisms whereby acidic microenvironment produced by enhanced glycolysis regulates gene expression to determine cell fate and has broad implications in the fields of regenerative medicine and cancer biology.

developmental biology↗