Biology subjects

Zhang, C.

Publications and source records attributed to Zhang, C..

At least 631 records · Page 35Linked to original sources

bioRxiv2022

Loss of Linker Histone H1 in the Maternal Genome Influences DEMETER-Mediated Demethylation and Affects the Endosperm DNA Methylation Landscape

The Arabidopsis DEMETER (DME) DNA glycosylase demethylates the central cell genome prior to fertilization. This epigenetic reconfiguration of the female gamete companion cell establishes gene imprinting in the endosperm and is essential for seed viability. DME demethylates small and genic-flanking transposons as well as intergenic and heterochromatin sequences, but how DME is recruited to these target loci remains unknown. H1.2 was identified as a DME-interacting protein in a yeast two-hybrid screen, and maternal genome H1 loss affects DNA methylation and expression of selected imprinted genes in the endosperm. Yet, the extent to which how H1 influences DME demethylation and gene imprinting in the Arabidopsis endosperm has not been investigated. Here, we showed that unlike in the vegetative cell, both canonical histone H1 variants are present in the central cell. Our endosperm methylome analysis revealed that without the maternal linker histones, DME-mediated demethylation is facilitated, particularly in the heterochromatin regions, indicating that H1-containing nucleosomes are barriers for DME demethylation. Loss of H1 in the maternal genome has a very limited effect on gene transcription or gene imprinting regulation in the endosperm; however, it variably influences euchromatin TE methylation and causes a slight hypermethylation and a reduced expression in selected imprinted genes. We conclude that loss of maternal H1 indirectly influences DME-mediated demethylation and endosperm DNA methylation landscape but does not appear to affect endosperm gene transcription and overall imprinting regulation.

plant biology↗

bioRxiv2022

The MTIST platform: a microbiome time series inference standardized test simulation, dataset, and scoring systems

The human gut microbiome is promising therapeutic target, but development of interventions is hampered by limited understanding of the microbial ecosystem. Therefore, recent years have seen a surge in the engineering of inference algorithms seeking to unravel rules of ecological interactions from metagenomic data. Research groups score algorithmic performance in a variety of different ways, however, there exists no unified framework to score and rank each inference approach. The machine learning field presents a useful solution to this issue: a unified set of validation data and accompanying scoring metric. Here, we present MTIST: a platform for benchmarking microbial ecosystem inference tools. We use a generalized Lotka-Volterra framework to simulate microbial abundances over time, akin to what would be obtained by quantitative metagenomic sequencing studies or lab experiments, to generate a massive in silico training dataset (MTIST) for algorithmic validation, as well as an "ecological sign" score (ES score) to rate them. MTIST comprises 24,570 time series of microbial abundance data packaged into 648 datasets. Together, the MTIST dataset and the ES score serve as a platform to develop and compare microbiome ecosystem inference approaches.

microbiology↗

bioRxiv2022

HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis

Melanomas are heterogeneous and adopt multiple transcriptional states that can confer an invasive phenotype and resistance to therapy. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity and tumor progression. Here we identify stress-induced HDAC8 activity as the driver of a neural crest stem cell (NCSC)-like transcriptional state that increased the formation of melanoma brain metastases (MBM). Exposure of melanocytes and melanoma cells to multiple different stresses led to HDAC8 activation, a switch to a NCSC gene expression signature and the adoption of an amoeboid, invasive phenotype. This cell state enhanced the survival of melanoma cells under shear stress conditions and increased the formation of metastases in the brain. scRNA-seq analyses showed that HDAC8 expression was correlated with the NCSC cell state in clinical MBM specimens. ATAC-Seq and ChIP-Seq analysis showed HDAC8 to alter chromatin structure by increasing H3K27ac and accessibility at c-Jun binding sites without changing global histone acetylation. The increased accessibility of Jun binding sites was paralleled by decreased H3K27ac and accessibility at MITF binding sites and loss of melanoma-lineage gene expression. Mass spectrometry-based acetylomics demonstrated that HDAC8 deacetylated the histone acetyltransferase (HAT) EP300 leading to its enzymatic inactivation. This, in turn, led to an increased binding of EP300 to Jun-transcriptional sites and decreased binding to MITF-transcriptional sites. Increased expression of EP300 decreased invasion and increased the sensitivity of melanoma cells to multiple stresses while inhibition of EP300 function increased invasion and resistance to stress. We identified HDAC8 as a novel mediator of transcriptional co-factor inactivation and chromatin accessibility that increases MBM development.

cancer biology↗

bioRxiv2022

Molecular recognition of two endogenous hormones by the human parathyroid hormone receptor-1

Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are two endogenous hormones recognized by PTH receptor -1 (PTH1R), a member of class B G protein couple receptors (GPCRs). Both PTH and PTHrP analogs including teriparatide and abaloparatide, are approved drugs for osteoporosis, but they exhibit distinct pharmacology. Here we report two cryo-EM structures of human PTH1R bound to PTH and PTHrP in the G protein-bound state at resolutions of 2.6 and 3.2 [A], respectively. Detailed analysis of these structures uncovers both common and unique features for the agonism of PTH and PTHrP. Molecular dynamics (MD) simulation and together with site-directed mutagenesis studies reveal the molecular basis of endogenous hormones recognition specificity and selectivity to PTH1R. These results provide a rational template for the clinical use of PTH and PTHrP analogs as an anabolic therapy for osteoporosis and other disorders.

biochemistry↗

bioRxiv2022

On the reliability of wearable technology: A tutorial on measuring heart rate and heart rate variability in the wild

Wearable sensors are quickly making their way into psychophysiological research, as they allow collecting longitudinal and ecologically valid data. The present tutorial considers fidelity of physiological measurement with wearable sensors, focusing on reliability. We elaborate why ensuring reliability for wearables is important and offer statistical tools for assessing wearable reliability for between participants and within-participant designs. The framework offered here is illustrated using several brands of commercially available heart rate sensors. Our hope is that by systematically quantifying measurement reliability, researchers will be able to make informed choices about specific wearable devices and measurement procedures that meet their research goals.

neuroscience↗

bioRxiv2022

Genome-scale mapping of functional genes and loci in bacteria for industrial phenotypes

Base editing, the targeted introduction of point mutations into cellular DNA, holds promise for improving genome-scale functional genome screening to single-nucleotide resolution. Current efforts in prokaryotes, however, remain confined to loss-of-function screens using the premature stop codons-mediated gene inactivation library, which falls far short of fully releasing the potential of base editors. Here, we developed a base editor-mediated functional single nucleotide variant screening pipeline in E. coli. We constructed a library with 31,123 sgRNAs targeting 462 stress response-related genes in E. coli, and screened for adaptive mutations under isobutanol and furfural selective conditions. Guided by the screening results, we successfully identified several known and novel functional mutations. Our pipeline might be expanded to the optimization of other phenotypes or the strain engineering in other microorganisms.

bioengineering↗

bioRxiv2022

CorA gene rearrangement triggered the salinity-driven speciation of Poseidoniales

Land-ocean interactions greatly impacted the evolution of coastal life on Earth. However, the geological forces and genetic mechanisms that shaped evolutionary adaptations and allowed microorganisms to inhabit coastal brackish waters remain largely unexplored. Here, we infer the evolutionary trajectory of the ubiquitous heterotrophic archaea Poseidoniales (Marine Group II archaea) across global aquatic habitats. Our results show that their brackish subgroups have evolved through the rearrangement of the magnesium transport gene corA that conferred osmotic-stress tolerance dated to over 600 million years ago. The coastal family of Poseidoniales showed a rapid increase in the evolutionary rate during and in the aftermath of the Cryogenian Snowball Earth (~700 million years ago), possibly in response to the enhanced phosphorus supply and the rise of algae. Our study highlights the close interplay between genetic changes and ecosystem transformations that boosted microbial diversification in the Neoproterozoic continental margins.

evolutionary biology↗

bioRxiv2022

Abnormal intrinsic neural timescale in Parkinson's disease

BACKGROUND: Numerous studies indicate altered peak latency of event-related potential and altered time variability of brain function network in Parkinsons disease (PD), and the intrinsic neural timescale estimated how long neural information stored in a local brain area has been specialized. However, it was unclear whether PD patients exhibited abnormal intrinsic timescales and accompanied with abnormal grey matter and whether PD patients exhibited different temporal feature at different stages. STUDY TYPE: Prospective. POPULATION: 74 PD patients, including 44 patients in the early stage (PD-ES) and 30 patients in the late stage (PD-LS), and 73 healthy controls (HC). SEQUENCE: 3.0T MRI scanner; prototypic T1 magnetization prepared rapid acquisition gradient echo (MPRAGE); resting-state fMRI. ASSESSMENT: the intrinsic timescales were estimated by using the magnitude of the autocorrelation of intrinsic neural signals. Voxel-based morphometry (VBM) was performed to calculate the grey matter volume (GMV) in the whole brain. STATISTICAL TEST: Analysis of variance (ANOVA); two-sample t-tests; Spearman rank correlation analysis; Mann-Whitney U test; Kruskal-Wallis H test. RESULTS: We identified that the PD group had abnormal intrinsic timescales in bilateral lingual and calcarine gyri, bilateral postcentral and precentral gyri, and the right middle cingulum gyrus, which correlated with the symptom severity and the GMV. Moreover, longer timescale in the right middle frontal gyrus were also found in the PD group. Increasingly, the PD-ES group had longer timescales in the anterior cortical regions, whereas the PD-LS group had shorter timescales in the posterior cortical regions. DATA CONCLUSION: Our findings suggest that PD patients exhibit abnormal intrinsic timescales in visual, sensorimotor, and cognitive systems and distinct patterns of intrinsic timescales and GMV in cerebral cortex at different stages, which might provide new insights for the neural substrate of PD.

neuroscience↗

bioRxiv2022

Guild-level microbiome signature associated with COVID-19 severity and prognosis

COVID-19 severity has been associated with alterations of the gut microbiota. However, the relationship between gut microbiome alterations and COVID-19 prognosis remains elusive. Here, we performed a genome-resolved metagenomic analysis on fecal samples collected from 300 in-hospital COVID-19 patients at time of admission. Among the 2,568 high quality metagenome-assembled genomes (HQMAGs), Redundancy Analysis identified 33 HQMAGs which showed differential distribution among mild, moderate, and severe/critical severity groups. Random Forest model based on these 33 HQMAGs classified patients from different severity groups (average AUC = 0.79). Co-abundance network analysis found that the 33 HQMAGs were organized as two competing guilds. Guild 1 harbored more genes for short-chain fatty acid biosynthesis, and fewer genes for virulence and antibiotic resistance, compared with Guild 2. Random Forest regression showed that these 33 HQMAGs at admission had the capacity to predict 8 clinical parameters, which are predictors for COVID-19 prognosis, at Day 7 in hospital. Moreover, the dominance of Guild 1 over Guild 2 at admission predicted the death/discharge outcome of the critical patients (AUC = 0.92). Random Forest models based on these 33 HQMAGs classified patients with different COVID-19 symptom severity, and differentiated COVID-19 patients from healthy subjects, non-COVID-19, and pneumonia controls in three independent datasets. Thus, this genome-based guild-level signature may facilitate early identification of hospitalized COVID-19 patients with high risk of more severe outcomes at time of admission.

microbiology↗

bioRxiv2022

GPCR Signaling Promotes a Stress-induced Genetic Program for Phenoptosis in C. elegans

How an organism dies is a fundamental yet poorly understood question in biology. An organism can die of many causes, including stress-induced phenoptosis, also defined as organismic death that is regulated by its genome-encoded programs. The mechanism of stress-induced phenoptosis is still largely unknown. Here we show that transient but severe freezing-thaw stress (FTS) in C. elegans induces rapid and robust phenoptosis that is regulated by G-protein coupled receptor (GPCR) signaling. RNAi screens identify the GPCR-encoding fshr-1 in mediating transcriptional responses to FTS. FSHR-1 increases ligand interaction upon FTS and activates a cyclic AMP-PKA cascade leading to a genetic program to promote organismic death under severe stress. FSHR-1/GPCR signaling up-regulates the bZIP-type transcription factor ZIP-10, linking FTS to expression of genes involved in lipid remodeling, proteostasis and aging. A mathematical model suggests that genes may promote organismic death under severe stress conditions, potentially benefiting growth of the clonal population with individuals less stressed and more reproductively privileged. Our studies reveal roles of FSHR-1/GPCR-mediated signaling in stress-induced gene expression and phenoptosis in C. elegans, providing empirical new insights into mechanisms of stress-induced phenoptosis with evolutionary implications.

developmental biology↗

bioRxiv2022

Mapping global land sharing-sparing patterns between human and wildlife

Understanding the global patterns of land sharing-sparing between humans and wildlife is essential for pragmatic conservation implementation, yet analytical foundations and indicator-based assessments are still lacking. By integrating distributions of 30,664 terrestrial vertebrates and human pressures, we provide a series of spatial explicit Human-Nature Indices (HNIs) before classifying the global lands into four categories. We found that the Co-occurring (C) regions, where lands are shared by humans and wildlife, are not insignificant (16.91% of global land). For land-sparing, the Diversity-intact (D) and the Anthropic (A) regions account for 45.64% and 1.41% of the land, respectively. The patterns of HNIs, varying considerably among taxonomic groups, are determined mainly by the expansion of human-dominated land use. Land sharing and sparing could work as complementary strategies to support biodiversity and human development toward ambitious and pragmatic 30 by 30 goals. Our results highlight that those regions should adopt different conservation strategies according to their sharing-sparing patterns and distribution of protected areas.

ecology↗

bioRxiv2022

STAT3 promotes RNA polymerase III-directed transcription by controlling the miR-106a-5p/TP73 axis

AbstractsDeregulation of Pol III products causes a range of diseases, including neural diseases and cancers. However, the pathways and factors that control Pol III-directed transcription have yet to be elucidated. Here, we show that STAT3 positively regulates the activities of Pol III-dependent transcription and cancer cell growth. RNA-seq analysis revealed that STAT3 inhibits the expression of TP73, a member of the p53 family. We found that TP73 is not only required for the regulation of Pol III-directed transcription mediated by STAT3 but also independently suppresses the synthesis of Pol III products. Mechanistically, TP73 can disrupt the assembly of TFIIIB subunits and inhibit their occupancies at Pol III target loci by interacting with TFIIB subunit TBP. MiR-106a-5p can activate Pol III-directed transcription by targeting the TP73 mRNA 3 UTR to reduce TP 73 expression. We show that STAT3 activates the expression of miR-106a-5p by binding to the microRNA promoter, indicating that miR-106a-5p links STAT3 to TP73 and Pol III transcription. Collectively, these findings indicate that STAT3 functions as a positive regulator in Pol III-directed transcription by controlling the miR-106a-5p/TP73 axis.

molecular biology↗

bioRxiv2022

Cognition through internal models: Mirror neurons as one manifestation of a broader mechanism

Cognition relies on transforming sensory inputs into a more generalizable understanding. Mirror neurons are proposed to underlie this process, yet they fail to explain many key features of human thinking and learning. Here we hypothesize that mirror-like responses are one limited view into a more general framework by which internal models of the world are built and used. We recorded populations of single neurons in the human posterior parietal cortex as a participant felt or observed diverse tactile stimuli. We found that mirror-like responses were fragile and embedded within a richer population response that encoded generalizable and compositional features of the stimuli. We speculate that populations of neurons support versatile understanding, not through mirroring, but instead by encoding representational building blocks of cognition. One-Sentence SummarySimilar neural responses during observed and experienced sensations are mediated by shared compositional building blocks, not mirror neurons.

neuroscience↗

bioRxiv2022

A small-molecule lycorine derivative reveals Na+/K+-ATPase α3 as an anti-obesity target

Obesity remains a severe global public health challenge, with contemporary therapeutic approaches primarily focusing on appetite suppression. Here, we discovered HLY72, a lycorine-derived small molecule that potently counteracts obesity in mice at doses without affecting food intake, by promoting sympathetic activation-mediated lipolysis and thermogenesis in adipose tissues. Mass spectrometry identified Na+/K+-ATPase (NKA) 3, the brain-specific isoform, as HLY72s target. Only blood-brain barrier-permeable NKA inhibitors reproduce HLY72s anti-obesity effects, and resistance to HLY72 treatment occurs specifically in NKA 3 (not 1) knockin mice harboring a HLY72-binding mutation. Similar to the chemical inhibition by HLY72, genetic inhibition of NKA 3 also effectively protects mice from diet-induced obesity. These findings point NKA 3 as a potent anti-obesity drug target and highlight HLY72s potential in treating and preventing obesity independent of appetite control.

physiology↗

bioRxiv2022

A megaprotein-based molecular bridge critical for lipid trafficking and cold resilience

Cells adapt to cold by increasing levels of unsaturated phospholipids and membrane fluidity through homeostatic mechanisms conserved in nearly all forms of life. As most eukaryotic enzymes for lipid synthesis and desaturation localize on endoplasmic reticulum (ER) membranes, it remains unknown how ER-resident lipids rapidly distribute to plasma membranes (PM). Here we report an exceptionally large and evolutionarily conserved protein LPD-3 in C. elegans that plays critical roles in lipid trafficking and cold resilience. We identified lpd-3 mutants in a mutagenesis screen for genetic suppressors of the lipid desaturase FAT-7, and found that the 452 kDa megaprotein LPD-3 bridges ER and PM, consisting of a structurally predicted hydrophobic tunnel for lipid trafficking. Loss of LPD-3 caused abnormal cellular distribution of phospholipids, diminished FAT-7 abundance, and organismic vulnerability to cold. These phenotypic defects of lpd-3 mutants were rescued by Lecithin comprising unsaturated phospholipids. Importantly, we found that deficient lpd-3 homologues in Zebrafish and mammalian cells led to defects similar to those observed in C. elegans. As mutations in KIAA1109/BLTP1, the human orthologue of lpd-3, cause Alkuraya-Kucinskas syndrome, we propose that the LPD-3 family proteins may serve as evolutionarily conserved "highway bridges" critical for ER-associated non-vesicular trafficking of lipids and resilience to cold stress in eukaryotic cells.

cell biology↗

bioRxiv2022

Detection of Frog virus 3 via the system integrating RPA-CRISPR/Cas12a-SPM with deep learning

Frog virus 3 (FV3, genera Ranavirus, family Iridoviridae), a double-stranded DNA virus, results in irreparable damage to biodiversity and significant economic losses to aquaculture. Although the existing FV3 detection methods are of high sensitivity and specificity, the complex procedure and requirement of expensive instruments limit their practical implantation. Herein, we develop a fast, easy-to-implement, highly sensitive, and point-of-care (POC) detection system for FV3. Combining recombinase polymerase amplification (RPA) and CRISPR/Cas12a, we achieve a limit of detection (LoD) of 100 aM (60.2 copies/L) by optimizing RPA primers and CRISPR RNAs (crRNAs). For POC detection, we build a smartphone microscopy (SPM) and achieve an LoD of 10 aM within 40 minutes. Four positive animal-derived samples with a quantitation cycle (Cq) value of quantitative PCR (qPCR) in the range of 13 to 32 are detectable by the proposed system. In addition, we deploy deep learning models for binary classification (positive or negative samples) and multiclass classification (different concentrations of FV3 and negative samples), achieving 100% and 98.75% accuracy, respectively. Without temperature regulation and expensive equipment, RPA-CRISPR/Cas12a combined with a smartphone readout and artificial intelligence (AI) assisted classification shows great potential for FV3 detection. This integrated system holds great promise for POC detection of aquatic DNA pathogens. HighlightsO_LIAn integrated DNA detection system is developed by combining RPA, CRISPR/Cas12a, smartphone microscopy, and deep learning. C_LIO_LIThe LoD of frog virus 3 is 10 aM within 40 min. C_LIO_LIThe detection system shows good performance on animal-derived samples. C_LI

molecular biology↗

bioRxiv2022

Dual inhibition of SHP2 and autophagy suppresses NF1-associated Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). MPNSTs develop within pre-existing benign plexiform neurofibromas (PNs). PNs are driven solely by biallelic NF1 loss eliciting RAS pathway activation and respond favorably to MEK inhibitor therapy. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST indicates that MEK inhibition has poor anti-tumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors was performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining pharmacological blockade of autophagy and SHP2 inhibition resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies can be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with autophagy inhibitors as a novel treatment approach for NF1 MPNSTs. Statement of significanceCurrently, no effective therapies exist for MPNST. We demonstrate intrinsic MPNST resistance to MEKi monotherapy and identify SHP2 inhibition as an actionable vulnerability upstream of RAS. Furthermore, anti-tumor effects are extended and enhanced by dual exposure to autophagy pathway inhibition. Validation of these results as the most effective therapy to date in multiple genetically engineered models and in orthotopic patient-derived xenografts justify a clinical trial to evaluate SHP2i in conjunction with autophagy inhibitors as a novel treatment approach for NF1 MPNSTs.

cancer biology↗

bioRxiv2022

Examining craniofacial variation among crispant and mutant zebrafish models of human skeletal diseases

Genetic diseases affecting the skeletal system present with a wide range of symptoms that make diagnosis and treatment difficult. Genome-wide association and sequencing studies have identified genes linked to human skeletal diseases. Gene editing of zebrafish models allows researchers to further examine the link between genotype and phenotype, with the long-term goal of improving diagnosis and treatment. While current automated tools enable rapid and in-depth phenotyping of the axial skeleton, characterizing the effects of mutations on the craniofacial skeleton has been more challenging. The objective of this study was to evaluate a semi-automated screening tool can be used to quantify craniofacial variations in zebrafish models using four genes that have been associated with human skeletal diseases (meox1, plod2, sost, and wnt16) as test cases. We used traditional landmarks to ground truth our dataset and pseudolandmarks to quantify variation across the 3D cranial skeleton between the groups (somatic crispant, germline mutant, and control fish). The proposed pipeline identified variation between the crispant or mutant fish and control fish for four genes. Variation in phenotypes parallel human craniofacial symptoms for two of the four genes tested. This study demonstrates the potential as well as the limitations of our pipeline as a screening tool to examine multi-dimensional phenotypes associated with the zebrafish craniofacial skeleton.

genetics↗