Biology subjects

Xie, W.

Publications and source records attributed to Xie, W..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Epigenetic remodeling and 3D chromatin reorganization governed by NKX2-1 drive neuroendocrine prostate cancer

A significant number of castration-resistant prostate cancer (CRPC) evolve into a neuroendocrine (NE) subtype termed NEPC, leading to resistance to androgen receptor (AR) pathway inhibitors and poor clinical outcomes. Through Hi-C analyses of a panel of patient-derived xenograft tumors, here we report drastically different 3D chromatin architectures between NEPC and CRPC samples. Such chromatin re-organization was faithfully recapitulated in vitro on isogenic cells undergoing NE transformation (NET). Mechanistically, neural transcription factor (TF) NKX2-1 is selectively and highly expressed in NEPC tumors and is indispensable for NET across various models. NKX2-1 preferentially binds to gene promoters, but it interacts with chromatin-pioneering factors such as FOXA2 at enhancer elements through chromatin looping, further strengthening FOXA2 binding at NE enhancers. Conversely, FOXA2 mediates regional DNA demethylation, attributing to NE enhancer priming and inducing NKX2-1 expression, forming a feed-forward loop. Single-cell multiome analyses of isogenic cells over time-course NET cells identify individual cells amid luminal-to-NE transformation, exhibiting intermediate epigenetic and transcriptome states. Lastly, NKX2-1/FOXA2 interacts with, and recruits CBP/p300 proteins to activate NE enhancers, and pharmacological inhibitors of CBP/p300 effectively blunted NE gene expression and abolished NEPC tumor growth. Thus, our study reports a hierarchical network of TFs governed by NKX2-1 in regulating the 2D and 3D chromatin re-organization during NET and uncovers a promising therapeutic approach to eradicate NEPC.

cancer biology↗

bioRxiv2024

An immunomechanical checkpoint PYK2 governs monocyte-to-macrophage differentiation in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic, stiff tumor microenvironment (TME), where tumor-associated macrophages (TAMs) drive ECM remodeling, progression, and immune evasion. The contribution of mechanical cues to monocyte differentiation into TAMs remains largely unexplored. Here we show that mechanical force is required for monocyte-to-macrophage differentiation. PYK2, as an innovative immunomechanical checkpoint, de facto governs this differentiation process. We demonstrated that PYK2 senses mechanical signals via Piezo1 and integrins, triggering F-actin polymerization and translocating to the nucleus to regulate mechanotransduction and differentiation genes (e.g., ACTR3, RELA). Targeted deletion of PYK2 impairs the differentiation and polarization of monocyte-derived macrophages, reshapes the PDAC microenvironment, and enhances the efficacy of anti-PD-1 immunotherapy. These findings underscore the critical role of mechanical cues in monocyte differentiation and suggest that targeting PYK2 is a promising strategy to modulate TAM function and improve immunotherapy outcomes in patients with PDAC. Statement of significanceThis study identifies PYK2 as an immunomechanical checkpoint that drives monocyte-to-macrophage differentiation in PDAC via Piezo1/integrin-mediated mechanical cues. Targeted deletion of PYK2 reshapes the PDAC microenvironment, and enhances the efficacy of anti-PD-1 immunotherapy, suggesting PYK2 as a promising therapeutic target to overcome immunotherapy resistance.

immunology↗

bioRxiv2024

Chromatin mimicry by human JC virus

Chronically persistent viruses are integral components of the organismal ecosystem in humans and animals 1 2. Many of these viruses replicate and accumulate within the cell nucleus 3. The nuclear location allows viruses to evade cytoplasmic host viral sensors and promotes viral replication 4. One of the unexplored and puzzling aspects of the viral nuclear lifecycle involves the viruss ability to deal with the physical constraints of nuclear architecture. To replicate and accumulate within the nucleus in large numbers sufficient for infection spreading, DNA viruses need to overcome the spatial limitations imposed by chromatin and the nuclear matrix. We found that one of the most widespread and potentially lethal human viruses, the JC polyomavirus 5, interferes with nuclear heterochromatin to create virus-occupied space. The JC viruss impact on heterochromatin is mediated by the viral nonstructural protein, Agnoprotein (Agno). Agnos interference with heterochromatin is governed by structurally diverse mimics of host epigenetic regulators that facilitate virus-induced chromatin reorganization and a dramatic decline in nuclear stiffness in the infected cells. The JCV epigenetic mimicry is critical for the virus infection, as evident from reduced replication of mimic-mutant viruses. Our data suggest that modulation of nuclear mechanical properties is a novel strategy enabling chronicity of the JC and possibly other nuclear virus infections.

microbiology↗

bioRxiv2024

Diverse defense systems synergistically drive the microbe-virus arms race in deep sea cold seeps

Cold seeps host diverse microbes and viruses with numerous unexplored defense and anti-defense systems. Analysis of 3,813 microbial and 13,336 viral genomes from 191 metagenomes across 17 cold seep sites reveals extensive microbial defense repertoires, with over 60% representing candidate systems. Experimental validation confirms that several candidates protect against viral infection. These defense systems frequently co-occur, suggesting potential synergistic interactions, and are broadly distributed across sediments. In response, viruses have evolved diverse anti-defense genes, and the concurrent presence of multiple viral and microbial systems highlights intricate coevolution. Functionally critical lineages, such as anaerobic methanotrophic archaea, sulfate-reducing bacteria, and diazotrophs, appear to modify their defensive strategies under ecological and environmental pressures; for example, sulfate-reducing bacteria harbor multiple Gabija systems while corresponding viruses carry anti-Gabija genes, illustrating specific coevolutionary adaptations. Overall, these findings underscore the critical role of virus-microbe interactions in shaping microbial metabolic functions and environmental adaptation in deep-sea ecosystems.

microbiology↗

bioRxiv2024

Unveiling multi-scale architectural features in single-cell Hi-C data using scCAFE

Single-cell Hi-C (scHi-C) has provided unprecedented insights into the heterogeneity of 3D genome organization. However, its sparse and noisy nature poses challenges for computational analyses, such as chromatin architectural feature identification. Here, we introduce scCAFE, a deep learning model for the multi-scale detection of architectural features at the single-cell level. scCAFE provides a unified framework for annotating chromatin loops, TAD-like domains (TLDs), and compartments across individual cells. Our model outperforms previous scHi-C loop calling methods and delivers accurate predictions of TLDs and compartments that are biologically consistent with previous studies. The resulting single-cell annotations also offer a measure to characterize the heterogeneity of different levels of architectural features across cell types. We leverage this heterogeneity and identify a series of marker loop anchors, which demonstrate the potential of the 3D genome data to annotate cell identities without the aid of simultaneously sequenced omics data. Overall, scCAFE not only serves as a useful tool for analyzing single-cell genomic architecture, but also paves the way for precise cell-type annotations solely based on 3D genome features.

bioinformatics↗

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

Super-Enhancer Driven ZFP36L1 Promotes PD-L1 Expression in Infiltrative Gastric Cancer

Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. Despite the widespread recognition of tumor immunotherapy in treating unresectable GC, challenges, including ineffective immunotherapy and drug resistance, persist. Therefore, understanding the regulatory mechanisms of PD-L1, particularly in the context of super-enhancers (SEs) and zinc finger protein 36 ring finger protein-like 1 (ZFP36L1) RNA-binding protein, is crucial. MethodsIn this study, we performed H3K27ac CUT&Tag sequencing, investigated the heterogeneity of SEs between two GC subtypes with differential growth patterns, and revealed the immune escape signatures driven by ZFP36L1-SE in infiltrative GC through SEs inhibitors treatment. The regulation of ZFP36L1 to PD-L1 was evaluated by quantitative PCR, western blot, flow cytometry and immunohistochemistry. Furthermore, we explored its regulatory mechanisms using a combination of molecular biology techniques, including luciferase reporter assay, GST/RNA pull-down, ChIP/RIP experiments, and in vivo functional assays. ResultsWe demonstrated that ZFP36L1, driven by an SE, enhances IFN-{gamma}-induced PD-L1 expression, with SPI1 identified as the specific transcription factor binding to ZFP36L1-SE. Mechanistically, ZFP36L1 binds to the adenylate uridylate-rich element in the 3UTR of HDAC3 mRNA, exacerbating its mRNA decay, and thereby facilitating PD-L1 abnormal transcriptional activation. ConclusionsCollectively, our findings provide mechanistic insights into the role of the SPI1- ZFP36L1-HDAC3-PD-L1 signaling axis in orchestrating immune escape mechanisms in GC, thereby offering valuable insights into the potential targets for immune checkpoint therapy in GC management.

cancer biology↗

bioRxiv2024

The novel role of Kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid-β plaques accumulation and tau protein hyperphosphorylation

Accumulation of amyloid {beta} (A{beta}) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimers disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular is uncertain. Here, we reported that serum Kallistatin concentrations were meaningfully higher in AD patients, with a higher concentration of fasting blood glucose and triglyceride. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower LTP in hippocampal CA1 neurons accompanied by increased A{beta} deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPAR{gamma} signaling, resulting in A{beta} cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3{beta}. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by down-regulating A{beta} and tau phosphorylation of KAL-TG mice. Collectively, our data clarified a novel mechanism for A{beta} accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD. HighlightsO_LIKallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype accompanied by increased A{beta} deposition and tau phosphorylation. C_LIO_LIKallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPAR{gamma} signaling. C_LIO_LIFenofibrate could alleviate cognitive memory impairment and down-regulate the serum Kallistatin level. C_LI

neuroscience↗

bioRxiv2024

Epigenetic delineation of the earliest cardiac lineage segregation by single-cell multi-omics

The mammalian heart is formed from multiple mesoderm-derived cell lineages. However, it remains largely unknown when and how the specification of mesoderm towards cardiac lineages is determined. Here, we systematically depict the transcriptional trajectories toward cardiomyocyte in early mouse embryo, and characterize the epigenetic landscapes underlying the early mesodermal lineage specification by single-cell multi-omics analyses. The analyses also reveal distinct core regulatory networks (CRN) in controlling specification of mesodermal lineages. We further demonstrate the essential role HAND1 and FOXF1 in driving the earliest cardiac progenitors specification. These key transcription factors occupy at distinct enhancers, but function synergistically and hierarchically to regulate the expression of cardiac-specific genes. In addition, HAND1 is required for exiting from the nascent mesoderm program, while FOXF1 is essential for driving cardiac differentiation during juxta-cardiac field (JCF) specification. Our findings establish transcriptional and epigenetic determinants specifying the early cardiac lineage, providing insights for the investigation of congenital heart defects.

molecular biology↗

bioRxiv2024

A high-continuity and annotated reference genome of allotetraploid Siberian wildrye (Elymus sibiricus L., Poaceae: Triticeae)

Elymus sibiricus L. (Siberian wildrye, Es), a species belonging to the wheat tribe, is extensively employed as forage and for the reclamation of degraded grasslands within the Qinghai-Tibet Plateau (QTP). This study provides a high-quality reference genome assembly for the allotetraploid Es, which is composed of 14 pseudomolecules with the total genome size of 6.57 Gb. Our finding suggest that large-scale bursts of retrotransposons are critical for the genome expansion of Es. We discovered a translocation event between the Es4H and Es6H chromosomes with a low frequency of combination. Phylogenetic analyses of 90 Es accessions and 25 diploid accessions representing proposed ancestors from various habitats revealed the existence of four distinct populations. We further provided support for the hypothesis that the QTP is the center of origin and genetic diversity for Es. Collectively, our study offers valuable insights into the evolution of Es, as well as providing genomic resources for genetic enhancement in the Elymus genus and wheat tribe.

genomics↗

bioRxiv2024

Chromosome-scale genome assembly of Apocynum pictum, a drought-tolerant medicinal plant from the Tarim Basin

Apocynum pictum Schrenk is a semi-shrub of the Apocynaceae family with a wide distribution throughout the Tarim Basin that holds significant ecological, medicinal, and economic values. Here, we report the assembly of its chromosome-level reference genome using Nanopore long-read, Illumina HiSeq paired-end, and high-throughput chromosome conformation capture sequencing. The final assembly is 225.32 Mb in length with a scaffold N50 of 19.64 Mb. It contains 23,147 protein-coding genes across 11 chromosomes, 21,148 of which (91.36%) have protein functional annotations. Comparative genomics analysis revealed that A. pictum diverged from the closely related species Apocynum venetum approximately 2.2 million years ago and has not undergone additional polyploidizations after the core eudicot WGT-{gamma} event. Karyotype evolution analysis was used to characterize interchromosomal rearrangements in representative Apocynaceae species and revealed that several A. pictum chromosomes were derived entirely from single chromosomes of the ancestral eudicot karyotype. Finally, we identified 50 members of the well-known stress-responsive WRKY transcription factor family and used transcriptomic data to document changes in their expression at two stages of drought stress, identifying a number of promising candidate genes. Overall, this study provides high-quality genomic resources for evolutionary and comparative genomics of the Apocynaceae, as well as initial molecular insights into the drought adaptation of this valuable desert plant.

genomics↗

bioRxiv2024

Environmental DNA from ethanol eluent of flowers reveals a widespread diversity in cowpea associated animal communities in Hainan Island

Cowpea (Vigna unguiculata (L.) Walp.), as an economical crop, is one of the important pillar industries of rural revitalization strategy in China. However, cowpea planting in China is often infested and damaged by many insects during growth, especially in Hainan region with a warm and wet tropical climate. Traditional monitoring methods with technical limitation could only detect a few common significant agricultural pests, how many kinds of species associated with cowpea is unknown. Here, we employed environmental DNA (eDNA) metabarcoding to characterize cowpea associated animal community-level diversity among six planting areas in Hainan. In all, 62 species were detected, of which 99.05% was Arthropoda, suggesting that Arthropods are the main groups interacting with cowpea. Moreover, we also detected 28 pests on cowpea, predominantly belonging to Thysanoptera, Lepidoptera, Diptera and Hemiptera, of which 20 pests were first reported and need more extra attention. Furthermore, clustering results indicated that there is a certain diversity of cowpea associated animals in different regions of Hainan, but the species composition was similar in the large planting areas due to the indiscriminate use of pesticides, which need further develop scientific pesticide applications to ensure adequate species diversity. This study represents the first molecular approach to investigate the cowpea associated animal communities and provides basic information for further scientific pesticide applications.

ecology↗

bioRxiv2024

Grayscale 4D Biomaterial Customization at High Resolution and Scale

Hydrogel biomaterials have proven indispensable for three-dimensional (3D) cell culture but have fallen short in replicating the innate physiochemical complexity of real tissue. Though traditional photolithography affords localized material manipulation, robust methods that govern when, where, and to what extent such phototailoring occurs throughout materials would be profoundly enabling towards fabricating more-realistic 3D tissue constructs. Here, we introduce "grayscale image z-stack-guided multiphoton optical-lithography" (GIZMO) as a generalizable and intuitive strategy to rapidly photomodulate materials in full 3D non-binary patterns at submicron resolutions spanning large volumes (>mm3). Highlighting its versatility, we employ GIZMO to variably photopattern biomolecule release from, protein immobilization to, and degradation within hydrogels based on biologically derived or synthetic grayscale image stacks with unprecedented complexity. We anticipate that GIZMO will enable new opportunities to probe and manipulate cell fates, as well as to engineer complex functional tissue.

bioengineering↗

bioRxiv2023

Deletion of Glyoxalase 1 exacerbates acetaminophen-induced hepatotoxicity in mice

Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC) has a narrow therapeutic window and early treatment is essential for satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late-presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end-products (AGEs) and consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase-1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in APAP mediated activation of RAGE and downstream cell-death cascades. Constitutive Glo-1 knockout mice (GKO) and a cofactor of Glo-1, {psi}-GSH, were employed as tools. Our findings show elevated oxidative stress, activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild type controls. A unique feature of the hepatic necrosis in GKO mice is the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than inflammation seen in wild type. The GSH surrogate and general antioxidant, {psi}-GSH alleviated APAP toxicity irrespective of Glo-1 status, suggesting that oxidative stress being the primary driver of APAP toxicity. Overall, exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against initial stages of APAP overdose.

pharmacology and toxicology↗

bioRxiv2023

Histone marks enable formation of immiscible phase-separated chromatin compartments

Eukaryotic chromatin is organized into compartments for gene expression regulation, but the underlying mechanisms remain unclear. Here, we demonstrate that multivalent H3K27me3 and its reader, CBX7-PRC1 complex, regulate facultative heterochromatin via a phase separation mechanism, similar to constitutive heterochromatin1. Facultative and constitutive heterochromatin represent distinct, coexisting condensates in nuclei. In vitro, H3K27me3- and H3K9me3-marked nucleosomal arrays and their reader complexes can phase separate into immiscible condensates that are analogous to the relationship between facultative and constitutive heterochromatin in vivo. Moreover, overexpression of CBX7-PRC1 causes aberrant chromatin compartmentalization in vivo as demonstrated by H3K9me3 CUT&Tag and up-regulation of genes related to cancer such as acute myeloblastic leukemia (AML). CBX7 inhibitor effectively inhibits cancer cell proliferation possibly through phase separation-mediated compartment reorganization. Our data demonstrated how the specificity of compartmentalization is achieved based on the formation of immiscible phase-separated condensates, and offer novel epigenetic mechanistic insights into tumor development.

biochemistry↗

bioRxiv2023

Epigenomic signatures as circulating and predictive biomarkers in sarcomatoid renal cell carcinoma

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are (1) a limited understanding of its gene regulatory programs and (2) difficulty identifying sarcomatoid differentiation on tumor biopsies due to spatial heterogeneity. To address these challenges, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries in tissue and plasma samples from 50 patients with RCC and healthy volunteers. We identified highly recurrent epigenomic reprogramming, as assessed by histone modifications and DNA methylation, that distinguishes sRCC from non-sarcomatoid RCC. Computational analysis of RCC epigenomic profiles and CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs. Analysis of two randomized clinical trials identified FOSL1 expression as a predictive biomarker of response to ICIs in RCC. Finally, we demonstrate that epigenomic signatures of sRCC are detectable in patient plasma, establishing an approach for blood-based diagnosis of this clinically important phenotype. These findings provide a framework for the discovery and non-invasive detection of epigenomic correlates of tumor histology via liquid biopsy.

genomics↗

bioRxiv2023

Harnessing Generative AI to Decode Enzyme Catalysis and Evolution for Enhanced Engineering

Enzymes, as paramount protein catalysts, occupy a central role in fostering remarkable progress across numerous fields. However, the intricacy of sequence-function relationships continues to obscure our grasp of enzyme behaviors and curtails our capabilities in rational enzyme engineering. Generative artificial intelligence (AI), known for its proficiency in handling intricate data distributions, holds the potential to offer novel perspectives in enzyme research. By applying generative models, we could discern elusive patterns within the vast sequence space and uncover new functional enzyme sequences. This review highlights the recent advancements in employing generative AI for enzyme sequence analysis. We delve into the impact of generative AI in predicting mutation effects on enzyme fitness, activity, and stability, rationalizing the laboratory evolution of de novo enzymes, decoding protein sequence semantics, and its applications in enzyme engineering. Notably, the prediction of enzyme activity and stability using natural enzyme sequences serves as a vital link, indicating how enzyme catalysis shapes enzyme evolution. Overall, we foresee that the integration of generative AI into enzyme studies will remarkably enhance our knowledge of enzymes and expedite the creation of superior biocatalysts.

bioinformatics↗

bioRxiv2023

High-resolution diploid 3D genome reconstruction using Pore-C data

In diploid organisms, spatial variations between homologous chromosomes are essential to many biological phenomena. Currently, it is still challenging to efficiently reconstruct a high-quality diploid 3D human genome. Here, we introduce Dip3D, reconstructing the diploid 3D human genome using Pore-C data of one sample. Dip3D has solved multiple problems in genome-wide SNV calling and haplo-tagging caused by the high sequencing error rates in Pore-C type data. Dip3D capitalizes on the high-order chromosomal interaction characteristics, enabling robust haplotype imputation and intricate haplotype-specific 3D structure discovery. Dip3D outperforms previous methods in data utilization rate, contact matrix resolution, and completeness by one order of magnitude. Moreover, Dip3D allows capturing haplotype high-order interactions that are unseen in Hi-C type data. We demonstrated the identified haplotype substructures such as Topologically Associating Domains (TADs) in the constructed 3D human genome, and unraveled connections between genic haplotype-specific high-order interactions and imbalanced allelic expression.

genomics↗