Biology subjects

Zhou, X.

Publications and source records attributed to Zhou, X..

At least 271 records · Page 15Linked to original sources

bioRxiv2024

Comprehensive mapping and modelling of the rice regulome landscape unveils the regulatory architecture underlying complex traits

Unraveling the regulatory mechanisms that govern complex traits is pivotal for advancing crop improvement. Here we present a comprehensive regulome atlas for rice (Oryza sativa), charting the chromatin accessibility across 23 distinct tissues from three representative varieties. Our study uncovers 117,176 unique open chromatin regions (OCRs), accounting for [~]15% of the rice genome, a notably higher proportion compared to previous reports in plants. Integrating RNA-seq data from matched tissues, we confidently predict 59,075 OCR-to-gene links, with enhancers constituting 69.54% of these associations, including many known enhancer-to-gene links. Leveraging this resource, we re-evaluate genome-wide association study results and discover a previously unknown function of OsbZIP06 in seed germination, which we subsequently confirm through experimental validation. We optimize deep learning models to decode regulatory grammar, achieving robust modeling of tissue-specific chromatin accessibility. This approach allows to predict cross-variety regulatory dynamics from genomic sequences, shedding light on the genetic underpinnings of cis-regulatory divergence and morphological disparities between varieties. Overall, our study establishes a foundational resource for rice functional genomics and precision molecular breeding, providing valuable insights into regulatory mechanisms governing complex traits.

genomics↗

bioRxiv2024

Dynamic Human Gut Microbiome and Immune Shifts During an Immersive Psychosocial Therapeutic Program

BackgroundDepression is a leading cause of disability worldwide yet its underlying factors, particularly microbial associations, are poorly understood. MethodsWe examined the longitudinal interplay between the microbiome and immune system in the context of depression during an immersive psychosocial intervention. 142 multi-omics samples were collected from 52 well-characterized participants before, during, and three months after a nine-day inquiry-based stress reduction program. ResultsWe found that depression was associated with both an increased presence of putatively pathogenic bacteria and reduced microbial beta-diversity. Following the intervention, we observed reductions in neuroinflammatory cytokines and improvements in several mental health indicators. Interestingly, participants with a Prevotella-dominant microbiome showed milder symptoms when depressed, along with a more resilient microbiome and more favorable inflammatory cytokine profile, including reduced levels of CXCL-1. ConclusionsOur findings reveal a protective link between the Prevotella-dominant microbiome and depression, associated with a less inflammatory environment and moderated symptoms. These insights, coupled with observed improvements in neuroinflammatory markers and mental health from the intervention, highlight potential avenues for microbiome-targeted therapies in depression management.

microbiology↗

bioRxiv2024

Hierarchical global and local auxin signals coordinate cellular interdigitation in Arabidopsis

The development of multicellular tissues requires both local and global coordination of cell polarization, however, the mechanisms underlying their interplay are poorly understood. In Arabidopsis, leaf epidermal pavement cells (PC) develop a puzzle-piece shape locally coordinated through apoplastic auxin signaling. Here we show auxin also globally coordinates interdigitation by activating the TIR1/AFB-dependent nuclear signaling pathway. This pathway promotes a transient maximum of auxin at the cotyledon tip, which then moves across the leaf activating local PC polarization, as demonstrated by locally uncaged auxin globally rescuing defects in tir1;afb1;afb2;afb4;afb5 mutant but not in tmk1;tmk2;tmk3;tmk4 mutants. Our findings show that hierarchically integrated global and local auxin signaling systems, which respectively depend on TIR1/AFB-dependent gene transcription in the nucleus and TMK-mediated rapid activation of ROP GTPases at the cell surface, control PC interdigitation patterns in Arabidopsis cotyledons, revealing a mechanism for coordinating a local cellular process with the development of whole tissues.

plant biology↗

bioRxiv2024

Transcriptional reprogramming deploys a compartmentalized "timebomb" in Catharanthus roseus to fend off chewing herbivores

The evolutionary arms-race between plants and insects has led to key adaptive innovations that drive diversification. Alkaloids are well-documented anti-herbivory compounds in plant chemical defenses, but how these specialized metabolites are allocated to cope with both biotic and abiotic stresses concomitantly is largely unknown. To examine how plants prioritize their metabolic resources responding to herbivory and cold, we integrated dietary toxicity bioassay in insects with co-expression analysis, hierarchical clustering, promoter assay, and protein-protein interaction in plants. Catharanthus roseus, a medicinal plant known for its insecticidal property against chewing herbivores, produces two terpenoid indole alkaloid monomers, vindoline and catharanthine. Individually, they exhibited negligible toxicity against Manduca sexta, a chewing herbivore; their condensed product, anhydrovinblastine, however, was highly toxic. Such unique insecticidal mode of action demonstrates that terpenoid indole alkaloid "timebomb" can only be activated when the two spatially isolated monomeric precursors are dimerized by herbivory. Without initial selection pressure and apparent fitness costs, this adaptive chemical defense against herbivory is innovative and sustainable. The biosynthesis of insecticidal terpenoid indole alkaloids is induced by herbivory but suppressed by cold. Here, we identified a transcription factor, Herbivore Induced Vindoline-gene Expression (HIVE), that coordinates the production of terpenoid indole alkaloids in response to herbivory and cold stress. The HIVE-mediated transcriptional reprogramming allows this herbaceous perennial to allocate their metabolic resources for chemical defense at a normal temperature, when herbivory pressure is high, but switches to cold tolerance under a cooler temperature, when insect infestation is secondary.

plant biology↗

bioRxiv2024

A multi-gene predictive model for the radiation sensitivity of nasopharyngeal carcinoma based on machine learning

BackgroundRadiotherapy resistance is a major obstacle to the long-term survival of nasopharyngeal cancer patients, as it is a primary cause of recurrence and metastasis. Identifying radiotherapy-associated biomarkers can help improve the survival prognosis of nasopharyngeal cancer patients. Consequently, discovering biomarkers associated with radiosensitization is crucial. MethodsWe evaluated 113 combinations of machine learning algorithms and ultimately selected 48 to construct a radiotherapy sensitivity score (NPC-RSS) that can predict radiosensitivity in nasopharyngeal cancer patients. Furthermore, we analyzed the relationship between NPC-RSS and the expression of genes associated with immune and radiotherapy sensitivity profiles. We employed GSEA and ssGSEA to investigate the connection between NPC-RSS and signaling pathways. ResultsWe selected the combined model glmBoost+NaiveBayes, which had the best AUC among 48 models, for our subsequent study. The NPC-RSS, built based on the 18 genes included in this model, can predict the results of the public dataset and the in-house dataset of Zhujiang Hospital, Southern Medical University, with considerable efficiency. The key genes of NPC-RSS are closely associated with immune characteristics, including chemokine and chemokine receptor families, and histocompatibility complex (MHC), and show more active immune processes. Meanwhile, these key genes were significantly associated with the expression of radiosensitization-related genes. Furthermore, GSVA and GSEA analyses demonstrated that different expression levels of key NPC-RSS genes influenced signaling pathways, such as the Wnt/{beta}-catenin signaling pathway, JAK-STAT signaling pathway,NF-kappa B signaling pathway and T cell receptor signaling pathway, which are associated with immunity and disease progression. The consistency of the expression of key genes SMARCA2 and CD9 with NPC-RSS was validated in in-house cell lines. The radiosensitive group, classified according to NPC-RSS, exhibited a more enriched and activated state of immune infiltration compared to the radioresistant group. Moreover, in single-cell samples, NPC-RSS was higher in the radiotherapy-sensitive group, with immune cells playing a predominant role. ConclusionsIn this study, we used machine learning to construct a predictive score, called NPC-RSS, associated with radiosensitivity in nasopharyngeal carcinoma patients; moreover, NPC-RSS is strongly associated with immune characteristics, expression of radiosensitivity-related genes, and signaling pathways related to disease progression. We hope that the NPC-RCC will enable more precise selection of the NPC population of potential beneficiaries of radiation therapy.

bioinformatics↗

bioRxiv2024

Unveiling the PHR-centered regulatory network orchestrating the phosphate starvation signaling in Chinese fir (Cunninghamia lanceolata)

Phosphorus (P) is an essential mineral element for plant growth and is absorbed and utilized in the form of inorganic phosphate (Pi). However, Pi deficiency largely restricts plant growth in forest ecosystems, while the molecular mechanism of Pi deficiency in woody plants remains unclear. Here, we show that PHOSPHATE STARVATION RESPONSE (PHRs) were central regulators of Pi starvation signaling in Chinese fir, a gymnosperm woody plant. Pi deficiency repressed the shoot growth by decreasing the net photosynthesis rate, reducing the size and number of needle leaves, suppressing the plant height, and reducing the biomass accumulation of shoots in Chinese fir seedlings. Thirteen Chinese fir PHRs (ClPHRs) were characterized, which evolved differently from model and angiosperm woody plants. ClPHRs did not respond to Pi deficiency at the transcriptional level, whereas three ClPHRs responded to Pi deficiency by increasing the nuclear/cytoplasmic protein abundance ratio. Four ClPHRs can restore Pi starvation signaling by activating transcription of AtPHT1;1 and AtPHT1;4 in the atphr1 mutant. Notably, ClPHR7, which is evolutionarily distinct from AtPHR1, was the only ClPHR that could respond to Pi deficiency and restore Pi starvation signals. ClPHR7 could also interact with SPX through protein-protein interaction analysis. Thus, the SPX-PHR regulatory module was also present in gymnosperm woody plants, but the exactly responsible proteins were evolutionarily different from those of model plants. In summary, our results revealed the function of the SPX-PHR regulatory module in Pi starvation signaling and provided genetic information for engineered woody plants with high Pi use efficiency.

plant biology↗

bioRxiv2024

Unique trajectory of gene family evolution from genomic analysis of nearly all known species in an ancient yeast lineage

Gene gains and losses are a major driver of genome evolution; their precise characterization can provide insights into the origin and diversification of major lineages. Here, we examined gene family evolution of 1,154 genomes from nearly all known species in the medically and technologically important yeast subphylum Saccharomycotina. We found that yeast gene family and genome evolution are distinct from plants, animals, and filamentous ascomycetes and are characterized by small genome sizes and smaller gene numbers but larger gene family sizes. Faster-evolving lineages (FELs) in yeasts experienced significantly higher rates of gene losses--commensurate with a narrowing of metabolic niche breadth--but higher speciation rates than their slower-evolving sister lineages (SELs). Gene families most often lost are those involved in mRNA splicing, carbohydrate metabolism, and cell division and are likely associated with intron loss, metabolic breadth, and non-canonical cell cycle processes. Our results highlight the significant role of gene family contractions in the evolution of yeast metabolism, genome function, and speciation, and suggest that gene family evolutionary trajectories have differed markedly across major eukaryotic lineages.

evolutionary biology↗

bioRxiv2024

ProTrek: Navigating the Protein Universe through Tri-Modal Contrastive Learning

ProTrek redefines protein exploration by seamlessly fusing sequence, structure, and natural language function (SSF) into an advanced tri-modal language model. Through contrastive learning, ProTrek bridges the gap between protein data and human understanding, enabling lightning-fast searches across nine SSF pairwise modality combinations. Trained on vastly larger datasets, ProTrek demonstrates quantum leaps in performance: (1) Elevating protein sequence-function interconversion by 30-60 fold; (2) Surpassing current alignment tools (i.e., Foldseek and MMseqs2) in both speed (100-fold acceleration) and accuracy, identifying functionally similar proteins with diverse structures; and (3) Outperforming ESM-2 in 9 of 11 downstream prediction tasks, setting new benchmarks in protein intelligence. These results suggest that ProTrek will become a core tool for protein searching, understanding, and analysis.

bioinformatics↗

bioRxiv2024

The curses of performing differential expression analysis using single-cell data

Differential expression analysis is pivotal in single-cell transcriptomics for unraveling cell-type- specific responses to stimuli. While numerous methods are available to identify differentially expressed genes in single-cell data, recent evaluations of both single-cell-specific methods and methods adapted from bulk studies have revealed significant shortcomings in performance. In this paper, we dissect the four major challenges in single-cell DE analysis: normalization, excessive zeros, donor effects, and cumulative biases. These "curses" underscore the limitations and conceptual pitfalls in existing workflows. In response, we introduce a novel paradigm addressing several of these issues.

bioinformatics↗

bioRxiv2024

SaprotHub: Making Protein Modeling Accessible to All Biologists

Training and deploying large-scale protein language models typically requires deep machine learning expertise -- a barrier for researchers outside this field. SaprotHub overcomes this challenge by offering an intuitive platform that facilitates training and prediction as well as storage and sharing of models. We provide the ColabSaprot framework built on Google Colab which potentially powers hundreds of protein training and prediction applications, enabling researchers to collaboratively build and share customized models.

bioinformatics↗

bioRxiv2024

Nuclear eNOS interacts with and S-nitrosates ADAR1 to modulate type I interferon signaling and endothelial function.

BackgroundNitric oxide (NO) generated by the endothelial NO synthase (eNOS) regulates vascular tone and endothelial homeostasis to counteract vascular inflammation. Most eNOS is localized at the cell membrane or in the Golgi apparatus, but the enzyme is also present in the endothelial cell nucleus. Here we assessed the relevance of nuclear eNOS and NO signaling for endothelial cell function. MethodseNOS gain- and loss-of-function approaches were combined with confocal microscopy, biochemical, histological and multi-omics analyses. The pathophysiological relevance of the findings was assessed in murine models of atherogenesis (ApoE-/- and partial carotid ligation) as well as in samples from patients with atherosclerosis. ResultseNOS was present in the nucleus of unstimulated human and murine endothelial cells (in vitro and ex vivo) and stimulation with vascular endothelial growth factor (VEGF) enhanced its nuclear localization. Co-immunoprecipitation studies coupled with proteomics revealed the association of nuclear eNOS with 81 proteins involved in RNA binding and processing. Among the latter was double-stranded RNA-specific adenosine deaminase (ADAR1), an enzyme involved in editing double-stranded RNA (dsRNA) via the deamination of adenosine (A) to inosine (I). ADAR1 was S-nitrosated in human endothelial cells, and the knockdown of eNOS resulted in altered ADAR1-mediated A-to-I editing and an increase in dsRNA. Mitochondrial antiviral signaling protein (MAVS) was the transcript most affected by eNOS depletion, and endothelial cells lacking eNOS accumulated dsRNA as well as MAVS protein aggregates. These changes resulted in activation of the type I interferon (IFN) signaling pathway and a marked downregulation of cell cycle-related genes. ADAR1 depletion elicited similar effects on the activation of type I IFN signaling. As a result, growth factor-stimulated cell proliferation was abrogated and basal as well as stimulated cell death were increased. Endothelial dysfunction in mice as well as in subjects with atherosclerosis was accompanied by the accumulation of dsRNA and the activation of the type I IFN signaling. Preserving NO bioavailability in vivo in an eNOS gain-of-function mouse model (Tyr657Phe eNOS) prevented these effects. ConclusionsOur findings have uncovered a novel mechanism linking nuclear eNOS-derived NO with the activity of ADAR1 to maintain vascular homeostasis. Reduced NO bioavailability results in the previously unrecognized activation of a type I IFN response in the endothelium, which contributes to atherogenesis.

physiology↗

bioRxiv2024

Genomic factors shaping codon usage across the Saccharomycotina subphylum

Codon usage bias, or the unequal use of synonymous codons, is observed across genes, genomes, and between species. The biased use of synonymous codons has been implicated in many cellular functions, such as translation dynamics and transcript stability, but can also be shaped by neutral forces. The Saccharomycotina, the fungal subphylum containing the yeasts Saccharomyces cerevisiae and Candida albicans, has been a model system for studying codon usage. We characterized codon usage across 1,154 strains from 1,051 species to gain insight into the biases, molecular mechanisms, evolution, and genomic features contributing to codon usage patterns across the subphylum. We found evidence of a general preference for A/T-ending codons and correlations between codon usage bias, GC content, and tRNA-ome size. Codon usage bias is also distinct between the 12 orders within the subphylum to such a degree that yeasts can be classified into orders with an accuracy greater than 90% using a machine learning algorithm trained on codon usage. We also characterized the degree to which codon usage bias is impacted by translational selection. Interestingly, the degree of translational selection was influenced by a combination of genome features and assembly metrics that included the number of coding sequences, BUSCO count, and genome length. Our analysis also revealed an extreme bias in codon usage in the Saccharomycodales associated with a lack of predicted arginine tRNAs. The order contains 24 species, and 23 are computationally predicted to lack tRNAs that decode CGN codons, leaving only the AGN codons to encode arginine. Analysis of Saccharomycodales gene expression, tRNA sequences, and codon evolution suggests that extreme avoidance of the CGN codons is associated with a decline in arginine tRNA function. Codon usage bias within the Saccharomycotina is generally consistent with previous investigations in fungi, which show a role for both genomic features and GC bias in shaping codon usage. However, we find cases of extreme codon usage preference and avoidance along yeast lineages, suggesting additional forces may be shaping the evolution of specific codons.

genomics↗

bioRxiv2024

Signatures of social pain empathy: general and process-specific brain-wide representations of social exclusion and separation

Empathy can be elicited by physiological pain, as well as in social contexts. Although physiological and different social contexts induce a strong subjective experience of empathy, the general and context-specific neural representations remain elusive. Here, we combine fMRI with multivariate pattern analysis to establish neurofunctional models for pain empathy triggered by social exclusion and separation. Our findings revealed both overlapping and distinct neural representations for social exclusion and separation empathy across cortical and subcortical regions. This study established an evolutionary model that traces the progression from social pain to physiological pain empathy. In conclusion, this study establishes neural decoding models for pain empathy evoked by social exclusion and social separation, revealing their neural foundations and interconnectedness of empathy induced by social and physiological stimuli. These findings deepen our understanding of the neurobiological mechanisms underlying social pain empathy and provide robust neuromarkers to precisely evaluate empathy across physiological and social domains.

neuroscience↗

bioRxiv2024

CPT2 mediated fatty acid oxidation is dispensable for humoral immunity

B cell activation is accompanied by dynamic metabolic reprogramming, supported by a multitude of nutrients that include glucose, amino acids and fatty acids. While several studies have indicated that fatty acid mitochondrial oxidation is critical for immune cell functions, contradictory findings have been reported. Carnitine palmitoyltransferase II (CPT2) is a critical enzyme for long-chain fatty acid oxidation in mitochondria. Here, we test the requirement of CPT2 for humoral immunity using a mouse model with a lymphocyte specific deletion of CPT2. Stable 13C isotope tracing reveals highly reduced fatty acid-derived citrate production in CPT2 deficient B cells. Yet, CPT2 deficiency has no significant impact on B cell development, B cell activation, germinal center formation, and antibody production upon either thymus-dependent or -independent antigen challenges. Together, our findings indicate that CPT2 mediated fatty acid oxidation is dispensable for humoral immunity, highlighting the metabolic flexibility of lymphocytes.

immunology↗

bioRxiv2024

A noncanonical GTPase signaling mechanism controls exit from mitosis in budding yeast

In the budding yeast Saccharomyces cerevisiae, exit from mitosis is coupled to spindle position to ensure successful genome partitioning between mother and daughter cell. This coupling occurs through a GTPase signaling cascade known as the mitotic exit network (MEN). The MEN senses spindle position via a Ras-like GTPase Tem1 which localizes to the spindle pole bodies (SPBs, yeast equivalent of centrosomes) during anaphase and signals to its effector protein kinase Cdc15. How Tem1 couples the status of spindle position to MEN activation is not fully understood. Here, we show that Cdc15 has a relatively weak preference for Tem1GTP and Tem1s nucleotide state does not change upon MEN activation. Instead, we find that Tem1s nucleotide cycle establishes a localization-based concentration difference in the cell where only Tem1GTP is recruited to the SPB, and spindle position regulates the MEN by controlling Tem1 localization. SPB localization of Tem1 primarily functions to promote Tem1-Cdc15 interaction for MEN activation by increasing the effective concentration of Tem1. Consistent with this model, we demonstrate that artificially tethering Tem1 to the SPB or concentrating Tem1 in the cytoplasm with genetically encoded multimeric nanoparticles could bypass the requirement of Tem1GTP and correct spindle position for MEN activation. This localization/concentration-based GTPase signaling mechanism for Tem1 differs from the canonical Ras-like GTPase signaling paradigm and is likely relevant to other localization-based signaling scenarios.

cell biology↗

bioRxiv2024

Brain-specific Gata4 downregulation in Greywick female mice models the metabolic subtype of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a heterogenous disorder characterized by reproductive and metabolic abnormalities. PCOS etiology remains poorly understood, although the hypothalamus is suspected to play a central role in many cases. Human genetic studies have also shown an association with the transcription factor-coding gene GATA4, but without providing a functional link. Here, we show that adult Greywick female mice may bridge this gap. These mice phenocopy PCOS with partial penetrance, due to serendipitous insertion of a Gata4 promoter-driven transgene in a strong enhancer region. Resulting robust transgene expression in subsets of hypothalamic neurons and glia impairs endogenous Gata4 expression, resulting in misexpression of genes linked to the control of fertility and food intake. We also show that this previously overlooked role of GATA4 in the hypothalamus can be replicated by conditional knockout approaches. Overall, this study sheds light not only on PCOS etiology but also on the role played by GATA4 in the central control of reproduction.

physiology↗

bioRxiv2024

Control of Inflammatory Response by Tissue Microenvironment

Inflammation is an essential defense response but operates at the cost of normal tissue functions. Whether and how the negative impact of inflammation is monitored remains largely unknown. Acidification of the tissue microenvironment is associated with inflammation. Here we investigated whether macrophages sense tissue acidification to adjust inflammatory responses. We found that acidic pH restructured the inflammatory response of macrophages in a gene-specific manner. We identified mammalian BRD4 as a novel intracellular pH sensor. Acidic pH disrupts the transcription condensates containing BRD4 and MED1, via histidine-enriched intrinsically disordered regions. Crucially, a decrease in macrophage intracellular pH is necessary and sufficient to regulate transcriptional condensates in vitro and in vivo, acting as negative feedback to regulate the inflammatory response. Collectively, these findings uncovered a pH-dependent switch in transcriptional condensates that enables environment-dependent control of inflammation, with a broader implication for calibrating the magnitude and quality of inflammation by the inflammatory cost. HighlightsO_LIAcidic pH regulates a switch-like gene-specific inflammatory response in macrophages C_LIO_LIAcidic pH impacts chromatin remodeling and transcription circuits to control inflammatory programs C_LIO_LIBRD4 transcriptional condensates are regulated by intracellular pH via the histidine-enriched intrinsically disordered region C_LIO_LITissue inflammation decreases intracellular pH and disrupts BRD4 condensates as a negative feedback C_LI

immunology↗

bioRxiv2024

Transplantation of exogenous mitochondria mitigates myocardial dysfunction after cardiac arrest

The incidence of post-cardiac arrest myocardial dysfunction (PAMD) is high, and there is currently no effective treatment available. This study aims to investigate the protective effects of exogenous mitochondrial transplantation. Exogenous mitochondrial transplantation can enhance myocardial function and improve the survival rate. Mechanistic studies suggest that mitochondrial transplantation can limit impairment in mitochondrial morphology, augment the activity of mitochondrial complexes II and IV, and raise ATP level. As well, mitochondrial therapy ameliorated oxidative stress imbalance, reduced myocardial injury, and thus improved PAMD after cardiopulmonary resuscitation (CPR).

systems biology↗