Biology subjects

Zhao, Q.

Publications and source records attributed to Zhao, Q..

At least 109 records · Page 6Linked to original sources

bioRxiv2024

Cross-Tissue Coordination between SLC Nucleoside Transporters Regulates Reproduction in Caenorhabditis elegans

Metabolism is fundamental to organism physiology and pathology. From the intricate network of metabolic reactions, diverse chemical molecules, collectively termed as metabolites, are produced. In multicellular organisms, metabolite communication between different tissues is vital for maintaining homeostasis and adaptation. However, the molecular mechanisms mediating these metabolite communications remain poorly understood. Here, we focus on nucleosides and nucleotides, essential metabolites involved in multiple cellular processes, and report the pivotal role of the SLC29A family of transporters in mediating nucleoside coordination between the soma and the germline. Through genetic analysis, we discovered that two Caenorhabditis elegans homologs of SLC29A transporters, Equilibrative Nucleoside Transporter ENT-1 and ENT-2, act in the germline and the intestine, respectively, to regulate reproduction. Their knockdown synergistically results in sterility. Further single-cell transcriptomic and targeted metabolomic profiling revealed that the ENT double knockdown specifically affects genes in the purine biosynthesis pathway and reduces the ratio of guanosine to adenosine levels. Importantly, guanosine supplementation into the body cavity/pseudocoelom through microinjection rescued the sterility caused by the ENT double knockdown, whereas adenosine microinjection had no effect. Together, these studies support guanosine as a rate limiting factor in the control of reproduction, uncover the previously unknown nucleoside/nucleotide communication between the soma and the germline essential for reproductive success, and highlight the significance of SLC-mediated cell-nonautonomous metabolite coordination in regulating organism physiology. Author SummaryMetabolism is essential for life, involving a complex network of chemical reactions that requires a well-organized system to maintain efficiency. This includes the optimal allocation of resources and the dynamic exchange of metabolic products between various compartments within an organism. Solute carriers (SLCs) are the largest family of transporters for metabolic products across the animal kingdom. In our research, we investigated how specific SLC transporters collaborate to move key metabolic products between different tissues. We identified two SLC transporters, Equilibrative Nucleoside Transporter ENT-1 and ENT-2, which are vital for transporting guanosine, a purine nucleoside, to support successful reproduction in the nematode Caenorhabditis elegans. We discovered that ENT-2 acts in the gut to export guanosine to the surrounding body cavity, while ENT-1 functions in the germline to import guanosine from the body cavity. When both transporters are disrupted, the animals experience significant reproductive defects. Our study underscores the importance of coordinated activity between SLC transporters in different tissues to maintain organism health. A breakdown in this communication can result in metabolic imbalances and physiological dysfunction.

genetics↗

bioRxiv2024

A cell and transcriptome atlas of the human arterial vasculature

Contiguous arterial segments show different propensities for different vascular pathologies, yet mechanisms explaining these fundamental differences remain unknown. We sought to build a transcriptomic, cellular, and spatial atlas of human arterial cells across multiple different arterial segments to understand these underlying differences. Analysis of multiple isogenic arterial segments from healthy donors reveals a significant stereotyped pattern of cell type-specific segmental heterogeneity in healthy arteries. Combining single cell analysis with spatial transcriptomic data reveals cellular heterogeneity not captured by commonly used cell-type marker genes. Determinants of arterial transcriptomic identities are predominantly encoded in fibroblasts and smooth muscle cells (SMC), and their differentially expressed genes are particularly enriched for different vascular disease-associated genetic risk- loci and risk-genes. Adventitial fibroblast-specific heterogeneity in gene expression coincides with a disproportionally large number of vascular disease genetic signals, suggesting a previously unrecognized role for this cell type in disease risk. Adult arterial cells from different segments cluster not by anatomical proximity, but by embryonic origin. Global regulon analysis of disease related segment-specific gene expression program in fibroblast and SMC enriches for binding sites of transcription factors that are developmental master regulators whose expression persists into adulthood, suggesting an important functional role of the same developmental master regulators in adult gene expression and disease. Lastly, non-coding transcriptomes across arterial cells contain extensive variation in lncRNAs expressed in cell type- and segment-specific patterns, rivaling heterogeneity in protein coding transcriptomes. Differentially expressed LncRNA demonstrate enrichment for non-coding genetic signals for vascular diseases, suggesting a potential global role of segmental specific LncRNAs in regulating inherited human vascular disease risk.

cell biology↗

bioRxiv2024

A robust unsupervised clustering approach for high-dimensional biological imaging data reveals shared drug-induced morphological signatures

Modern biology increasingly relies on large-scale screening to generate high dimensional datasets with potential to accelerate discovery. However, analysing these complex datasets remains challenging, particularly in applications where the underlying structure and groupings are unknown, and high dimensionality introduces noise and artifacts that make follow up studies difficult to prioritise. Here, we present an unsupervised consensus clustering tool that quantifies biologically meaningful patterns based on multi-scale data organisation to guide decision-making in high-throughput screening. Using large-scale drug screening data in cancer cell lines and bacterium model, we demonstrate its ability to use diverse data inputs to prioritize robust drug clusters with shared biological mechanisms and conserved drug responses. This method addresses key limitations associated with prioritising robust, actionable hits from scalable screening data.

bioinformatics↗

bioRxiv2024

Sex-specific differences in brain activity dynamics of youth with a family history of substance use disorder

An individuals risk of substance use disorder (SUD) is shaped by a complex interplay of potent biosocial factors. Current neurodevelopmental models posit vulnerability to SUD in youth is due to an overreactive reward system and reduced inhibitory control. Having a family history of SUD is a particularly strong risk factor, yet few studies have explored its impact on brain function and structure prior to substance exposure. Herein, we utilized a network control theory approach to quantify sex-specific differences in brain activity dynamics in youth with and without a family history of SUD, drawn from a large cohort of substance-naive youth from the Adolescent Brain Cognitive Development Study. We summarize brain dynamics by calculating transition energy, which probes the ease with which a whole brain, region or network drives the brain towards a specific spatial pattern of activation (i.e., brain state). Our findings reveal that a family history of SUD is associated with alterations in the brains dynamics wherein: i) independent of sex, certain regions transition energies are higher in those with a family history of SUD and ii) there exist sex-specific differences in SUD family history groups at multiple levels of transition energy (global, network, and regional). Family history-by-sex effects reveal that energetic demand is increased in females with a family history of SUD and decreased in males with a family history of SUD, compared to their same-sex counterparts with no SUD family history. Specifically, we localize these effects to higher energetic demands of the default mode network in females with a family history of SUD and lower energetic demands of attention networks in males with a family history of SUD. These results suggest a family history of SUD may increase reward saliency in males and decrease efficiency of top-down inhibitory control in females. This work could be used to inform personalized intervention strategies that may target differing cognitive mechanisms that predispose individuals to the development of SUD.

neuroscience↗

bioRxiv2024

High-throughput Image-based Clustering of CAR-T/Tumor Cocultures for Rapid and Facile Hit Identification

AO_SCPLOWBSTRACTC_SCPLOWChimeric antigen receptor T cell is important because of its potential to treat various diseases. As deep learning continues to advance, using unsupervised methods to classify medical images has become a significant focus because collecting high-quality labeled data for medical images is labor-intensive and time-consuming. Beyond the need for accurate labeling, there is a desire to explore the underlying characteristics of the data, even when labels may be ambiguous or uncertain. To address these challenges, we present a novel approach that combines image clustering with an insightful explanation of how these clusters are formed. Our method employs a U-net combined with a clustering algorithm to segment the dataset into different groups. After clustering, we use various techniques to interpret and elucidate the results. Moreover, our paper introduces a unique dataset focused on cell data, specifically highlighting the developmental patterns of cancer cells and T cells under various experimental conditions. This dataset offers a rich source of information and presents a complex challenge for image classification due to the diversity of conditions and cell behaviors involved. Our study thoroughly compares different architectural models on this new dataset, demonstrating the superior performance of our proposed architecture. Through experimental analysis and ablation studies, we provide substantial evidence of the benefits offered by our architecture, not only in terms of accuracy but also in its ability to reveal deeper insights into the data. This work advances the field of image classification and opens new possibilities for understanding complex biological processes through computer vision.

cell biology↗

bioRxiv2024

Competition and Compromise between Exogenous Probiotics and Native Microbiota

Probiotic interventions are effective strategies to modulate the gut microbiome, but how exogenous probiotics compete with native gut microbiota remains elusive. Here, we use a mouse model and a well-documented probiotic Bifidobacterium animalis subsp. lactis V9 (BV9) to mechanistically investigate its competitive strategies. We perform metagenomic and whole genome sequencing of stool samples and isolated BV9, longitudinally collected from 24 mice orally administered with BV9 and different diets. Results show that a high-fiber diet most effectively supports the colonization of BV9, where BV9 selectively competes with Parabacteroides distasonis (P. distasonis), rather than extensively with other gut bacteria. By comparing the genomic structures of BV9 and P. distasonis isolated during the washout period, we infer their co-evolution mechanisms, highlighting their competition and compromise in utilizing inulin-derived glucose. Finally, our in vitro co-culture experiments validate such competitive dynamics. This study fills a critical gap in our understanding of niche competition in colonization.

microbiology↗

bioRxiv2024

CaMutQC: An R Package for Integrative Quality Control of Cancer Somatic Mutations

The quality control and filtration of cancer somatic mutations (CAMs), including the elimination of false positives resulting from technical bias and the selection of key mutation candidates, is crucial for downstream analysis in cancer genomics. Due to diverse needs and the absence of standardized filtering criteria, the filtering strategies employed vary from study to study, often leading to reduced efficiency, accuracy, and comparability across similar analyses. Here we present CaMutQC, a heuristic quality control and soft-filtering R/Bioconductor package for CAMs. With CaMutQC, the removal of false positives, selection of potential mutation candidates, and Tumor Mutation Burden estimation can be executed in a single line of code, using default or customized parameters. A filter report and a code log generated after the filtration process assist with recording and comparison. The application of CaMutQC on a Whole-exome Sequencing (WES) benchmark dataset demonstrated its impressive capability by eliminating 85.55% of false positive mutations while retaining 90.72% of true positive mutations. Additionally, an extra 11.56% of true positive mutations were recused by the union strategy embedded in CaMutQC. CaMutQC is now available through Bioconductor at https://bioconductor.org/packages/CaMutQC/ under the GPL v3 license, and it will be updated regularly to incorporate top filtration strategy and parameter sets shared within the community.

bioinformatics↗

bioRxiv2024

Translation efficiency covariation across cell types is a conserved organizing principle of mammalian transcriptomes

Characterizing shared patterns of RNA expression between genes across conditions has led to the discovery of regulatory networks and novel biological functions. However, it is unclear if such coordination extends to translation. Here, we uniformly analyzed 3,819 ribosome profiling datasets from 117 human and 94 mouse tissues and cell lines. We introduce the concept of translation efficiency covariation (TEC), identifying coordinated translation patterns across cell types. We nominate candidate mechanisms driving shared patterns of translation regulation. TEC is conserved across human and mouse cells and uncovers gene functions that are not evident from RNA or protein co-expression. Moreover, our observations indicate that proteins that physically interact are highly enriched for positive covariation at both translational and transcriptional levels. Our findings establish TEC as a conserved organizing principle of mammalian transcriptomes.

bioinformatics↗

bioRxiv2024

Unraveling the Role of Ctla-4 in Intestinal Immune Homeostasis: Insights from a novel Zebrafish Model of Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a chronic and relapsing immune-mediated disorder characterized by intestinal inflammation and epithelial injury. The underlying causes of IBD are not fully understood, but genetic factors have implicated in genome-wide association studies, including CTLA-4, an essential negative regulator of T cell activation. However, establishing a direct link between CTLA-4 and IBD has been challenging due to the early lethality of CTLA-4 knockout mice. In this study, we identified zebrafish Ctla-4 homolog and investigated its role in maintaining intestinal immune homeostasis by generating a Ctla-4-deficient (ctla-4-/-) zebrafish line. These mutant zebrafish exhibited reduced weight, along with impaired epithelial barrier integrity and lymphocytic infiltration in their intestines. Transcriptomics analysis revealed upregulation of inflammation-related genes, disturbing immune system homeostasis. Moreover, single-cell RNA-sequencing analysis indicated increased Th2 cells and interleukin 13 expression, along with decreased innate lymphoid cells and upregulated proinflammatory cytokines. Additionally, Ctla-4-deficient zebrafish exhibited reduced diversity and an altered composition of the intestinal microbiota. All these phenotypes closely resemble those found in mammalian IBD. Lastly, supplementation with Ctla-4-Ig successfully alleviated intestinal inflammation in these mutants. Altogether, our findings demonstrate the pivotal role of Ctla-4 in maintaining intestinal homeostasis. Additionally, they offer substantial evidence linking CTLA-4 to IBD and establish a novel zebrafish model for investigating both the pathogenesis and potential treatments.

immunology↗

bioRxiv2024

YTHDF2 upregulation and relocation dictate CD8 T cell polyfunctionality in tumor immunity

Epigenetic traits impact the antitumor function of CD8 T cells, yet whether and how RNA methylation programs engage in T cell immunity is poorly understood. Here we show that the N6-methyladenosine (m6A) RNA reader YTHDF2 is highly expressed in early effector or effector-like CD8 T cells and is partially distributed in the nucleus. YTHDF2 loss in T cells exacerbates tumor progression and confers unresponsiveness to PD-1 blockade in mice and humans. In addition to initiating RNA decay for mitochondrial fitness, YTHDF2 can orchestrate chromatin regulation to promote T cell polyfunctionality. YTHDF2-mediatd preservation of gene transcription arises from the interaction of YTHDF2 with IKZF1/3. Accordingly, immunotherapy-induced efficacy could be largely restored in YTHDF2-deficient T cells through combinational use of lenalidomide. Moreover, m6A recognition is fundamental for YTHDF2 translocation to the nucleus and autoregulation at the RNA level. Thus, YTHDF2 coordinates epitranscriptional and transcriptional networks to potentiate T cell immunity. HighlightsO_LIYTHDF2 expression and distribution underpin the threshold for bona fide CD8 T cell effector response C_LIO_LICanonical YTHDF2-mRNA decay pathway alleviates mitochondrial stress and CD8 T cell exhaustion C_LIO_LINuclear YTHDF2 sequesters IKZF1/3-mediated transcriptional repression to safeguard CD8 T cell polyfunctionality C_LIO_LIThe tumoricidal activity of YTHDF2-deficient CD8 T cells could be repaired through the synergy of anti-PD-1 and lenalidomide C_LI

immunology↗

bioRxiv2024

Smooth muscle expression of RNA editing enzyme ADAR1 controls vascular integrity and progression of atherosclerosis

Mapping the genomic architecture of complex disease has been predicated on the understanding that genetic variants influence disease risk through modifying gene expression. However, recent discoveries have revealed that a significant burden of disease heritability in common autoinflammatory disorders and coronary artery disease (CAD) is mediated through genetic variation modifying post-transcriptional modification of RNA through adenosine-to-inosine (A-to-I) RNA editing. This common RNA modification is catalyzed by ADAR enzymes, where ADAR1 edits specific immunogenic double stranded RNA (dsRNA) to prevent activation of the double strand RNA (dsRNA) sensor MDA5 (IFIH1) and stimulation of an interferon stimulated gene (ISG) response. Multiple lines of human genetic data indicate impaired RNA editing and increased dsRNA sensing by MDA5 to be an important mechanism of CAD risk. Here, we provide a crucial link between observations in human genetics and mechanistic cell biology leading to progression of CAD. Through analysis of human atherosclerotic plaque and culture of human coronary artery vascular smooth muscle cells (SMCs) we implicate the SMC to have a distinct requirement for RNA editing, and that MDA5 activation regulates SMC phenotypic modulation. Through generation of a conditional SMC specific Adar1 deletion mouse model on a pro-atherosclerosis background with additional constitutive deletion of MDA5 (Ifih1), and with incorporation of single cell RNA sequencing cellular profiling, we further show that Adar1 controls SMC phenotypic state by regulating Mda5 activation, is required to maintain vascular integrity, and controls progression of atherosclerosis and vascular calcification. Finally, we further corroborate our findings in a large human carotid endarterectomy dataset (Athero-Express) where we show that ISG activation is strongly associated with decreased plaque stability, increased SMC phenotypic modulation, and increased plaque calcification. Through this work, we describe a fundamental mechanism of CAD, where cell type and context specific RNA editing and sensing of dsRNA mediates disease progression, bridging our understanding of human genetics and disease causality. One Sentence SummarySmooth muscle expression of RNA editing enzyme ADAR1 regulates activation of double strand RNA sensor MDA5 in novel mechanism of atherosclerosis.

genomics↗

bioRxiv2024

Engineering programmable CAR-T cells with tunable controls as fail-safe mechanisms during cancer immunotherapy

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in treating various cancers, but significant risks of severe adverse effects remain. In this study, we present a synthetic biology toolbox for engineering CAR-T cells with tunable and controllable features to mitigate these risks. Using this toolbox, we programmed cytotoxic CAR-T cells to be turned on and off using synthetic genes with tetracycline response elements, referred to as iOnCAR and iOffCAR. We achieved temporal regulation of CAR expression using the synthetic Notch receptor system and "AND-gate" programs, which allow for additional control using doxycycline. We also engineered cooperation among T cells through CD4 help to CD8 T cells in targeting cancer cells via synthetic Notch receptors controlled by doxycycline treatment. Additionally, we developed a T cell fratricide system by triggering a genetic "Battle Royale" mechanism that enables CAR-T cells to eliminate each other. In this system, surviving T cells become activated, proliferate, and display high cytotoxicity to target cells. In conclusion, our synthetic biology toolbox provides targeted fail-safe solutions for improving the safety and potency of CAR-T cell therapies by integrating different genetic circuits with a commonly used antibiotic.

immunology↗

bioRxiv2024

Fat body-derived cytokine Upd2 controls disciplined migration of tracheal stem cells in Drosophila

Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis. Drosophila tracheal progenitors are adult stem cells that migrate posteriorly along the dorsal trunk to replenish degenerating branches that disperse the FGF mitogen. However, it is currently unknown how the overall anterior-to-posterior directionality of such migration is controlled. Here we show that individual progenitor cells migrate together in a concerted, disciplined manner, a behavior that is dependent on the neighboring fat body. We identify the fat body-derived cytokine, Upd2, in targeting and inducing JAK/STAT signaling in tracheal progenitors to maintain their directional migration. Perturbation of either Upd2 production in fat body or JAK/STAT signaling in trachea causes aberrant bidirectional migration of tracheal progenitors. We show that JAK/STAT signaling promotes the expression of genes involved in planar cell polarity leading to asymmetric localization of Fat in progenitor cells. We provide evidence that Upd2 transport requires Rab5- and Rab7-mediated endocytic sorting and Lbm-dependent vesicle trafficking. Our study thus uncovers an inter-organ communication in the control of disciplined migration of tracheal progenitor cells, a process that requires vesicular trafficking of fat body-derived cytokine Upd2 and JAK/STAT signaling-mediated activation of PCP genes.

developmental biology↗

bioRxiv2024

Fibrillarin modulates fetal hemoglobin silencing

Decoding the molecular mechanisms underlying human fetal ({gamma}) globin gene silencing impacts therapeutic strategies for {beta}-thalassemia and sickle cell disease. Here, we identified a nucleolar protein, fibrillarin (FBL), which mediates the methylation of glutamine104 in histone H2A and functions as a repressor of the {gamma}-globin gene in cultured erythroid cells, including those from {beta}-thalassemia patients. Conditional Fbl depletion in adult {beta}-YAC transgenic mice or in {beta}IVS-2-654-thalassemic mice reactivated the human {gamma}-globin gene or murine embryonic globin expression, respectively, which corrects hematologic and pathologic defects in {beta}-thalassemic mice. We showed that FBL plays a dual role in activating BCL11A expression and repressing {gamma}-globin gene expression, which is dependent on its histone methyltransferase activity. Our study may provide an alternative strategy for therapeutic targeted treatment of {beta}-hemoglobinopathies.

molecular biology↗

bioRxiv2024

An efficient method for visualizing the plaques of Bdellovibrio bacteriovorus

Bdellovibrio bacteriovorus preys upon other Gram-negative bacteria. This obligate predator is recognized as a living antibiotic to control the rising problem of antibiotic resistance. Plaque forming units (PFU) counting is commonly used to determine the viable numbers of B. bacteriovorus. However, nearly 3-days incubation is always necessary for getting the single, obvious plaques on the double layer agar plate. This time-consuming procedure greatly impedes the purification and enumeration efficiency of B. bacteriovorus. In this work, we evaluated the advantages of fluorescent prey on the plaque visualization of the predator. Our study reveals that plaques of the B. bacteriovorus have already formed before they could be monitored by eyes on the double layer agar plate. The regular single plaques are easily observed under the enhanced background of fluorescent prey lawn in 1.5 days, reducing nearly half of the time consumption in the purification and enumeration of B. bacteriovorus. In addition, it also provides some paradigms for modeling and testing the subtle predation process on the solid medium. IMPORTANCEThe viability of predator Bdellovibrio bacteriovorus is typically suggested by the lysis of the prey bacteria on the double layer agar plate. However, long period incubation is necessary to get single obvious plaques of B. bacteriovorus. Here, we found that plaques are already generated before it can be monitored by eyes. The plaques are obvious on the enhanced background of the double layer agar plate in the presence of fluorescent prey under UV light. We confirmed that the utilization of fluorescence labeled prey bacteria reduces the time spent on the isolation, purification, and enumeration of the predator B. bacteriovorus on the double layer agar plate.

microbiology↗

bioRxiv2024

Unveiling the mechanisms of black phosphorus nanosheets-induced viable but non-culturable state in Bacillus tropicus

The release of black phosphorus (BP) nanosheets has raised concerns regarding potential ecological risks. Previous studies have confirmed their toxicity to bacteria, but discrepancies were observed between results obtained from the growth curve and colony forming unit (CFU) methods, indicating the possibility of bacterial cells entering a viable but non-culturable (VBNC) state induced by BP nanosheets. To accurately assess the risks, it is crucial to understand the underlying mechanisms. In this study, we investigated the effect of BP nanosheets on Bacillus tropicus, a gram-positive bacterium, using transcriptome sequencing and biological assays. Our findings revealed that BP nanosheets caused minimal cell death but predominately induced the VBNC state in most cells. At the transcriptional level, we observed significant down-regulation of pathways associated with cellular metabolism and respiratory chain in response to BP nanosheet treatment. Bacterial cells in the VBNC state exhibited depressed respiration to maintain basal cellular activity. Additionally, the reduced cellular respiration and metabolic activity were associated with a decrease in antibiotic susceptibility of the bacteria. These results provide new insights into the antibacterial mechanisms of BP nanosheets and emphasize the necessity of employing appropriate approaches, beyond the traditional CFU method, to assess the bacterial toxicity of nanomaterials. Environmental implicationBacteria play a crucial role as indicators in ecological risk assessment. Although numerous studies have highlighted the exceptional antibacterial properties of black phosphorus (BP) nanosheets, the unique viable but non-culturable (VBNC) state of bacteria is often overlooked when evaluating the ecological risks of nanomaterial, including BP nanosheets. In our study, we found that BP nanosheets can induce Bacillus tropicus into a VBNC state by suppressing cellular metabolism- and respiratory chain-related pathways, shedding light on their ecological risk assessment implications. This finding underscores the importance of utilizing appropriate approaches in evaluating the bacterial toxicity of nanomaterials.

pharmacology and toxicology↗

bioRxiv2024

Haploid-phased chromosomal telomere to telomere genome assembly of Uncaria rhynchophylla accelerating gene mining on the biosynthesis of medicinal alkaloids

Recorded traditionary medicinal plants contain important resources, including many natural medicinal alkaloids, for new medicine discovery and development. Uncaria genus is such a woody plant, with a high medicinal value in alkaloids, e.g. (iso)rhynchophylline. Natural alkaloids contents usually vary between germplasms and are affected by the growth environment, which requires a genomics solution to understand the genetic and environmental factors that influence alkaloid production in more detail. Here, we have dissected the haploid-resolved chromosomal T2T genome assembly of Uncaria rhynchophylla with a size of [~]634 Mb and contig N50 of 26 Mb using PacBio HiFi long-reads and Hi-C and anchored the contigs on 22 pairs of confirmed chromosomes. This genome contains 56% repeat sequences and [~]2,9000 protein-encoding genes. U. rhynchophylla diverged from a common ancestor shared with Coffea around 20 million years ago and contains expanded and contracted gene families associated with secondary metabolites and plant-associated defenses. We constructed the pathway for (iso)rhynchophylline biosynthesis with genes mined from the genome and comparative transcriptomes. 53 alkaloids out of 2,578 metabolites were identified in (iso)rhynchophylline biosynthesis, where eight differentially expressed genes were the key for regulating the catalytic steps leading to alkaloid abundance difference between tissues. The chromosome-level genome and pathways of (iso)rhynchophylline constructed in this study provide a genetic basis and guidance for further breeding improvements and the development of pharmaceutical alkaloids.

genomics↗

bioRxiv2024

Associations Between Prenatal Vitamin D and Placental Gene Expression

BackgroundVitamin D is a hormone regulating gene transcription. Prenatal vitamin D has been linked to immune and vascular function in the placenta, a key organ of pregnancy. To date, studies of vitamin D and placental gene expression have focused on a limited number of candidate genes. Transcriptome-wide RNA sequencing can provide a more complete representation of the placental effects of vitamin D. ObjectiveWe investigated the association between prenatal vitamin D levels and placental gene expression in a large, prospective pregnancy cohort. MethodsParticipants were recruited in Shelby County, Tennessee in the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study. Vitamin D level (plasma total 25-hydroxyvitatmin D, [25(OH)D]) was measured at mid-pregnancy (16-28 weeks gestation) and delivery. Placenta samples were collected at birth. RNA was isolated and sequenced. We identified differentially expressed genes (DEGs) using adjusted linear regression models. We also conducted weighted gene co-expression network analysis (WGCNA). ResultsThe median 25(OH)D of participants was 21.8 ng/mL at mid-pregnancy (N=774, IQR: 15.4-26.5 ng/mL) and 23.6 ng/mL at delivery (N=753, IQR: 16.8-29.1 ng/mL). Placental expression of 25 DEGs was associated with 25(OH)D at mid-pregnancy, but no DEG was associated with 25(OH)D at delivery. DEGs were related to energy metabolism, cytoskeletal function, and RNA transcription. Using WGCNA, we identified 2 gene modules whose expression was associated with 25(OH)D at mid-pregnancy and 1 module associated with 25(OH)D at delivery. These modules were enriched for genes related to mitochondrial and cytoskeletal function, and were regulated by transcription factors including ARNT2, BHLHE40, FOSL2, JUND, and NFKB1. ConclusionsOur results indicate that 25(OH)D during mid-pregnancy, but not at delivery, is associated with placental gene expression at birth. Future research is needed to investigate a potential role of vitamin D in programming placental mitochondrial metabolism, intracellular transport, and transcriptional regulation during pregnancy.

developmental biology↗