Biology subjects

Xu, G.

Publications and source records attributed to Xu, G..

At least 109 records · Page 6Linked to original sources

bioRxiv2021

Gene losses may contribute to subterranean adaptations in naked mole-rat and blind mole-rat

The naked mole-rats (Heterocephalus glaber, NMRs) and the blind mole-rats (Spalax galili, BMRs) are representative subterranean rodents that evolved many extraordinary traits, including hypoxia tolerance, longevity and cancer resistance. Although a batch of candidate loci responsible for these intriguing traits have been uncovered by genomic studies, many of them are limited to functional modifications of intact genes and little is known about the contributions of other genetic makeups. Here, to address this issue, we focused on gene losses (unitary pseudogenes) and systematically analyzed gene losses in NMRs and BMRs, as well as their respective terrestrial relatives, guinea pigs and rats, in a genome-wide scale. 167, 139, 341 and 112 pseudogenes were identified in NMRs, BMRs, guinea pigs and rats, respectively. Functional enrichment analysis identified 4 shared and 2 species-specific enriched functional groups (EFGs) in subterranean lineages. The pseudogenes in these EFGs might be associated with either regressive (e.g. visual system) or adaptive (e.g. altered DNA damage response) traits. In addition, several pseudogenes including TNNI3K and PDE5A, might be associated with their specific cardiac features observed in subterranean linages. Furthermore, we observed 20 convergent gene losses in NMRs and BMRs. Given that the functional investigations of these genes are generally scarce, we provided functional evidence that independent loss of TRIM17 in NMRs and BMRs might be beneficial for neuronal survival under hypoxia, supporting the positive role of eliminating TRIM17 function in hypoxia adaptation. We also demonstrated that pseudogenes, together with positively selected genes, reinforced subterranean adaptations cooperatively. Overall, our study provides new insights into the molecular underpinnings of subterranean adaptations and highlights the importance of gene losses in mammalian evolution.

evolutionary biology↗

bioRxiv2021

A UAV-based high-throughput phenotyping approach to assess time-series nitrogen responses and identify traits associated genetic components in maize

Advancements in the use of genome-wide markers have provided new opportunities for dissecting the genetic components that control phenotypic trait variation. However, cost-effectively characterizing agronomically important phenotypic traits on a large scale remains a bottleneck. Unmanned aerial vehicle (UAV)-based high-throughput phenotyping has recently become a prominent method, as it allows large numbers of plants to be analyzed in a time-series manner. In this experiment, 233 inbred lines from the maize diversity panel were grown in a replicated incomplete block under both nitrogen-limited conditions and following conventional agronomic practices. UAV images were collected during different plant developmental stages throughout the growing season. A pipeline for extracting plot-level images, filtering images to remove non-foliage elements, and calculating canopy coverage and greenness ratings based on vegetation indices (VIs) was developed. After applying the pipeline, about half a million plot-level image clips were obtained for 12 different time points. High correlations were detected between VIs and ground truth physiological and yield-related traits collected from the same plots, i.e., Vegetative Index (VEG) vs. leaf nitrogen levels (Pearson correlation coefficient, R = 0.73), Woebbecke index vs. leaf area (R = -0.52), and Visible Atmospherically Resistant Index (VARI) vs. 20 kernel weight - a yield component trait (R = 0.40). The genome-wide association study was performed using canopy coverage and each of the VIs at each date, resulting in N = 29 unique genomic regions associated with image extracted traits from three or more of the 12 total time points. A candidate gene Zm00001d031997, a maize homolog of the Arabidopsis HCF244 (high chlorophyll fluorescence 244), located underneath the leading SNPs of the canopy coverage associated signals that were repeatedly detected under both nitrogen conditions. The plot-level time-series phenotypic data and the trait-associated genes provide great opportunities to advance plant science and to facilitate plant breeding.

plant biology↗

bioRxiv2021

OPUS-X: An Open-Source Toolkit for Protein Torsion Angles, Secondary Structure, Solvent Accessibility, Contact Map Predictions, and 3D Folding

In this paper, we report an open-source toolkit for protein 3D structure modeling, named OPUS-X. It contains three modules: OPUS-TASS2, which predicts protein torsion angles, secondary structure and solvent accessibility; OPUS-Contact, which measures the distance and orientations information between different residue pairs; and OPUS-Fold2, which uses the constraints derived from the first two modules to guide folding. OPUS-TASS2 is an upgraded version of our previous method OPUSS-TASS (Bioinformatics 2020, 36 (20), 5021-5026). OPUS-TASS2 integrates protein global structure information and significantly outperforms OPUS-TASS. OPUS-Contact combines multiple raw co-evolutionary features with protein 1D features predicted by OPUS-TASS2, and delivers better results than the open-source state-of-the-art method trRosetta. OPUS-Fold2 is a complementary version of our previous method OPUS-Fold (J. Chem. Theory Comput. 2020, 16 (6), 3970-3976). OPUS-Fold2 is a gradient-based protein folding framework based on the differentiable energy terms in opposed to OPUS-Fold that is a sampling-based method used to deal with the non-differentiable terms. OPUS-Fold2 exhibits comparable performance to the Rosetta folding protocol in trRosetta when using identical inputs. OPUS-Fold2 is written in Python and TensorFlow2.4, which is user-friendly to any source-code level modification. The code and pre-trained models of OPUS-X can be downloaded from https://github.com/OPUS-MaLab/opus_x.

bioinformatics↗

bioRxiv2021

Genome-wide mediation analysis: bridging the dividebetween genotype and phenotype via transcriptomicdata in maize

Mapping genotype to phenotype is an essential topic in genetics and genomics research. As the Omics data become increasingly available, genome-wide association study (GWAS) has been widely applied to establish the relationship between genotype and phenotype. However, signals detected by GWAS usually span broad genomic regions with many underneath candidate genes, making it challenging to interpret and validate the molecular functions of the candidate genes. Under the context of genetics research, we hypothesized a causal chain from genotype to phenotype partially mediated by intermediate molecular processes, i.e., gene expression. To test this hypothesis, we applied the high dimensional mediation analysis, a class of causal inference method with an assumed causal chain from the exposure to the mediator to the outcome, and implemented it to the maize diversity panel (N=280 lines). Using 40 publicly available agronomic traits, 66 newly generated metabolic traits, and published RNA-seq data from seven different tissues, we detected N=736 unique mediating genes, explaining an average of 12.7% phenotypic variance due to mediation. Noticeably, 83/736 (11%) genes were identified in mediating more than one trait, suggesting the prevalence of pleiotropic mediating effects. Among those pleiotropic mediators, benzox-azinone synthesis 13 (Bx13), a well-characterized gene encoding a 2-oxoglutarate-dependent dioxygenase, was identified mediating 40 agronomic and metabolic traits in different tissues. Further genetic and genomic analyses of the Bx13 and adjacent mediating genes suggested a 3D co-regulation modulation likely affect their expression levels and eventually lead to phenotypic consequences. Our results suggested the genome-wide mediation analysis is a powerful tool to integrate Omics data in providing causal inference to connect genotype to phenotype.

genetics↗

bioRxiv2021

Metabolic characteristics of taste differences under the soil and hydroponic cultures of sweet potato leaves by using non-targeted metabolomics

Sweet potato leaves are consumed as green leafy vegetables in most of the world due to their nutritional and functional values, and the taste characteristics determine their commodity value and consumer acceptance. However, the metabolic composition and formation mechanism of taste quality in its leaves are not clear. In this study, we found that sweet potato leaves under different growing patterns, soil culture and hydroponic culture, which result in different taste quality. In particular, the taste quality in leafy sweet potato was effectively improved under hydroponic culture. Meanwhile, we further profiled metabolites in leaves of sweet potatoes under different growing patterns by using GC-QToF-MS. A total of 200 metabolites were identified, covering most of the metabolic pathways in plants. A comparison of the good taste and poor taste of sweet potato leaves resulted in 71 metabolites related to taste quality formation. In addition, the leaves with poor taste had lower levels of metabolites regarding amino acids metabolism, whereas was accompanied by high levels of metabolites in carbohydrates and secondary metabolism. This study provides new insights into the improvement of taste quality in leafy sweet potato.

plant biology↗

bioRxiv2021

The CLASSY family controls tissue-specific DNA methylation patterns in Arabidopsis

DNA methylation shapes the epigenetic landscape of the genome, plays critical roles in regulating gene expression, and ensures transposon silencing. As evidenced by the numerous defects associated with aberrant DNA methylation landscapes, establishing proper tissue-specific methylation patterns is critical. Yet, how such differences arise remains a largely open question in both plants and animals. Here we demonstrate that CLASSY1-4 (CLSY1-4), four locus-specific regulators of DNA methylation that are differentially expressed during plant development, play major roles in controlling tissue-specific DNA methylation patterns. Depending on the tissue, the genetic requirements for specific CLSYs differ significantly and, on a global scale, certain clsy mutants are sufficient to largely shift the epigenetic landscape between tissues. Together, these findings not only reveal substantial epigenetic diversity between tissues, but assign these changes to specific CLSY proteins, revealing how locus-specific targeting combined with tissue-specific expression enables the CLSYs to generate epigenetic diversity during plant development.

plant biology↗

bioRxiv2020

Binding strength and hydrogen bond numbers between Covid-19 RBD and HVR of antibody

The global battle against the Covid-19 pandemic relies strongly on the human defence of antibody, which is assumed to bind the antigens Receptor Binding Domain with its Hypervariable Region. Due to the similarity to other viruses such as SARS, however, our understanding of the antibody-virus interaction has been largely limited to the genomic sequencing, which poses serious challenges to the containment, vaccine exploration and rapid serum testing. Based on the physical/chemical nature of the interaction, infrared spectroscopy was employed to reveal the binding disparity, when unusual temperature dependence was discovered from the 1550cm-1 absorption band, attributed to the hydrogen bonds by carboxyl/amino groups, binding the SARS-CoV-2 spike protein and closely resembled SARS-CoV-2 or SARS-CoV-1 antibodies. The infrared absorption intensity, associated with the number of hydrogen bonds, was found to increase sharply between 27{degrees}C and 31{degrees}C, with the relative absorbance matches at 37{degrees}C the hydrogen bonding numbers of the two antibody types (19 vs 12). Meanwhile the ratio of bonds at 27{degrees}C, calculated by thermodynamic exponentials rather than by the laymans guess, produces at least 5% inaccuracy. As a result, the specificity of the SARS-CoV-2 antibody will be more conclusive beyond 31{degrees}C, instead of at the usual room temperature of 20{degrees}C - 25{degrees}C, when the vaccine research and antibody diagnosis would likely be undermined. Beyond genomic sequencing, the temperature dependence, as well as the bond number match at 37{degrees}C between relative absorbance and the hydrogen bonding numbers of the two antibody types, are not only of clinical significance in particular, but also of a sample for the physical/chemical understanding of the vaccine-antibody interactions in general.

microbiology↗

bioRxiv2020

PHAIR, A biosensor for pH measurement in air-liquid interface of human airway epithelial cells

1In many biological systems, pH can be used as a parameter to understand and study cell dynamics. However, measuring pH in live cell culture is limited by the sensor ion specificity, proximity to the cell surface, and scalability. Commercially available pH sensors are difficult to integrate into a small-scale cell culture system due to their size and are not cost-effective for disposable use. We made PHAIR - a new pH sensor that uses a micro-wire format to measure pH in vitro human airway cell culture. Tungsten micro-wires were used as the working electrodes, and silver micro-wires with a silver/silver chloride coating were used as a pseudo reference electrode. pH sensitivity, in a wide and narrow range, and stability of these sensors were tested in common standard buffer solutions as well as in culture media of human airway epithelial cells grown at the air-liquid interface in a 24 well cell culture plate. When measuring the pH of cells grown under basal and challenging conditions using PHAIR, cell viability and cytokine responses were not affected. Our results confirm that micro-wires-based sensors have the capacity for miniaturization, and detection of diverse ions while maintaining sensitivity. This suggests the broad application of PHAIR in various biological experimental settings.

bioengineering↗

bioRxiv2020

Large-scale single-cell analysis reveals critical immune characteristics of COVID-19 patients

Dysfunctional immune response in the COVID-19 patients is a recurrent theme impacting symptoms and mortality, yet the detailed understanding of pertinent immune cells is not complete. We applied single-cell RNA sequencing to 284 samples from 205 COVID-19 patients and controls to create a comprehensive immune landscape. Lymphopenia and active T and B cell responses were found to coexist and associated with age, sex and their interactions with COVID-19. Diverse epithelial and immune cell types were observed to be virus-positive and showed dramatic transcriptomic changes. Elevation of ANXA1 and S100A9 in virus-positive squamous epithelial cells may enable the initiation of neutrophil and macrophage responses via the ANXA1-FPR1 and S100A8/9-TLR4 axes. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis and designing effective therapeutic strategies for COVID-19. HIGHLIGHTSO_LILarge-scale scRNA-seq analysis depicts the immune landscape of COVID-19 C_LIO_LILymphopenia and active T and B cell responses coexist and are shaped by age and sex C_LIO_LISARS-CoV-2 infects diverse epithelial and immune cells, inducing distinct responses C_LIO_LICytokine storms with systemic S100A8/A9 are associated with COVID-19 severity C_LI

genomics↗

bioRxiv2020

Transferrin receptor (Tfr1) ablation in satellite cells impacts skeletal muscle regeneration through the activation of ferroptosis

Satellite cells (SCs) are critical to the postnatal development and skeletal muscle regeneration. Inactivation of SCs is linked with the skeletal muscle loss. Leveraging on the RNAseq screening, transferrin receptor (Tfr1) is identified to be associated with muscle/SC ageing and the declined regeneration potential. Muscle-specific deletion of Tfr1 results in the growth retardation, metabolic disorder and lethality, shedding light on the importance of Tfr1 in skeletal muscle physiology. Here, our investigation reported that conditional SC-ablation of Tfr1 leads to the SCs inactivation and skeletal muscle regeneration defects, followed by the labile iron accumulation, de novo lipogenesis via fibroadipogenic progenitors (FAPs) and Gpx4/Nrf2-mediated ROS-scavenger defects. These abnormal phenomena, such as Hmox1-mediated myoglobin degradation, Tfr1-Slc39a14 functional switch and the activation of unsaturated fatty acid biosynthesis pathway are orchestrated with the occurrence of ferroptosis in skeletal muscle. Ferroptosis may further prevent SC proliferation and skeletal muscle regeneration. Ferrostatin-1, a ferroptosis inhibitor could not rescue Tfr1-ablation induced ferroptosis. However, intramuscular administration of lentivirus expressing Tfr1 could partially reduce labile iron accumulation, decrease de novo lipogenesis and promote skeletal muscle regeneration. Most importantly, Tfr1/Slc39a14 functional switch, labile iron accumulation and fatty acid biosynthesis are recapitulated in aged skeletal muscle of rodents, indicating that ferroptosis occurs in the skeletal muscles of aged rodents. The present study also bridges the gap between pathogenesis of iron and functional defects in the skeletal muscle, providing mechanistic information to develop anti-aging strategies. One Sentence SummaryConditional ablation of Tfr1 in satellite cells (SCs) results in the SC inactivation, skeletal muscle regeneration defects, labile iron accumulation, and unsaturated fatty acid biosynthesis, leading to the activation of ferroptosis, which is recapitulated in skeletal muscles of aged rodents to be a new cell death form identified in skeletal muscle and sheds light on the development of novel anti-ageing strategies.

cell biology↗

bioRxiv2020

PD-L1 lncRNA splice promotes lung adenocarcinoma progression via enhancing c-Myc activity

Although blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the efficacy of such immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism underlying the limited efficacy of PD-L1 inhibitors remains unclear. Here, we show that human lung adenocarcinoma, regardless of PD-L1 protein positive or negative, all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) via alternative splicing, which promotes lung adenocarcinoma proliferation and metastasis. PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFN{gamma} in a manner similar to PD-L1 mRNA. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc directly binds to c-Myc and enhances c-Myc transcriptional activity downstream in lung adenocarcinoma cells. Our results provide targeting PD-L1-lnc-c-Myc axis as a novel strategy for lung cancer therapy.

cancer biology↗

bioRxiv2020

Interaction network of SARS-CoV-2 with host receptome through spike protein

Host cellular receptors are key determinants of virus tropism and pathogenesis. Virus utilizes multiple receptors for attachment, entry, or specific host responses. However, other than ACE2, little is known about SARS-CoV-2 receptors. Furthermore, ACE2 cannot easily interpret the multi-organ tropisms of SARS-CoV-2 nor the clinical differences between SARS-CoV-2 and SARS-CoV. To identify host cell receptors involved in SARS-CoV-2 interactions, we performed genomic receptor profiling to screen almost all human membrane proteins, with SARS-CoV-2 capsid spike (S) protein as the target. Twelve receptors were identified, including ACE2. Most receptors bind at least two domains on S protein, the receptor-binding-domain (RBD) and the N-terminal-domain (NTD), suggesting both are critical for virus-host interaction. Ectopic expression of ASGR1 or KREMEN1 is sufficient to enable entry of SARS-CoV-2, but not SARS-CoV and MERS-CoV. Analyzing single-cell transcriptome profiles from COVID-19 patients revealed that virus susceptibility in airway epithelial ciliated and secretory cells and immune macrophages highly correlates with expression of ACE2, KREMEN1 and ASGR1 respectively, and ACE2/ASGR1/KREMEN1 (ASK) together displayed a much better correlation than any individual receptor. Based on modeling of systemic SARS-CoV-2 host interactions through S receptors, we revealed ASK correlation with SARS-CoV-2 multi-organ tropism and provided potential explanations for various COVID-19 symptoms. Our study identified a panel of SARS-CoV-2 receptors with diverse binding properties, biological functions, and clinical correlations or implications, including ASGR1 and KREMEN1 as the alternative entry receptors, providing insights into critical interactions of SARS-CoV-2 with host, as well as a useful resource and potential drug targets for COVID-19 investigation.

microbiology↗

bioRxiv2020

Cell-line-specific network models of ER+ breast cancer identify PI3Kα inhibitor sensitivity factors and drug combinations

Durable control of invasive solid tumors necessitates identifying therapeutic resistance mechanisms and effective drug combinations. A promising approach to tackle the cancer drug resistance problem is to build mechanistic mathematical models of the signaling network of cancer cells, and explicitly model the dynamics of information flow through this network under distinct genetic conditions and in response to perturbations. In this work, we used a network-based mathematical model to identify sensitivity factors and drug combinations for the PI3K inhibitor alpelisib, which was recently approved for ER+ PIK3CA mutant breast cancer. We experimentally validated the model-predicted efficacious combination of alpelisib and BH3 mimetics (e.g. MCL1 inhibitors) in ER+ breast cancer cell lines. We also experimentally validated the reduced sensitivity to alpelisib caused by FOXO3 knockdown, which is a novel potential resistance mechanism. Our experimental results showed cell line-specific sensitivity to the combination of alpelisib and BH3 mimetics, which was driven by the choice of BH3 mimetics. We find that cell lines were sensitive to the addition of either MCL1 inhibitor s63845 alone or in combination with BCL-XL/BCL-2 inhibitor navitoclax, and that the need for the combination of both BH3 mimetics was predicted by the expression of BCL-XL. Based on these results, we developed cell line-specific network models that are able to recapitulate the observed differential response to alpelisib and BH3 mimetics, and also incorporate the most recent knowledge on resistance and response to PI3K inhibitors. Overall, we present an approach for the development, experimental testing, and refining of mathematical models, which we apply to the context of PI3K inhibitor drug resistance in breast cancer. Our approach predicted and validated PI3K inhibitor sensitivity factors (FOXO3 knockdown) and drug combinations (BH3 mimetics), and illustrates that network-based mathematical models can contribute to overcoming the challenge of cancer drug resistance.

cancer biology↗

bioRxiv2020

Cross-regulation between RpfG and HtsHs to regulate antibiotic biosynthesis in Lysobacter

Bacterial two-component systems (TCSs) sense and respond to environmental changes and modulate downstream gene expression. However, the mechanism of cross-talk between multiple TCSs is unclear. In this study, we report a previously uncharacterized mechanism by which the TCS protein RpfG interacts with hybrid two-component system (HyTCS) proteins HtsH1, HtsH2 and HtsH3 to regulate antibiotic biosynthesis in Lysobacter. RpfG, a phosphodiesterase (PDE), can degrade c-di-GMP to 5-pGpG and can regulate antibiotic heat-stable antifungal factor (HSAF) biosynthesis in a PDE- independent manner. Thus, we wondered whether RpfG regulate HSAF biosynthesis through interactions with other factors. Subsequently, we demonstrated that RpfG interacts with three HyTCS proteins (HtsH1, HtsH2 and HtsH3), that can inhibit the PDE enzymatic activity of RpfG. Importantly, deletion of htsH1, htsH2 and htsH3 resulted in significantly decreased HSAF production, and we showed that HtsH1, HtsH2 and HtsH3 depend on their phosphorylation activity to directly regulate HSAF biosynthesis gene expression. Our results reveal that RpfG does not depend on PDE activity to regulate HSAF biosynthesis, rather it interacts with HtsH1, HtsH2 and HtsH3 to do so, a regulatory mechanism that may be a conserved paradigm in Lysobacter and Xanthomonas.

microbiology↗

bioRxiv2020

Proto-sex locus in large yellow croaker provides insights into early evolution of the sex chromosome

Autosomal origins of heterogametic sex chromosomes have been inferred frequently from suppressed recombination and gene degeneration manifested in incompletely differentiated sex chromosomes. However, the initial transition of an autosome region to a proto-sex locus has been not explored in depth. By assembling and analyzing a chromosome-level draft genome, we found a recent (evolved 0.26 million years ago), highly homologous, and dmrt1 containing sex-determination locus with slightly reduced recombination in large yellow croaker (Larimichthys crocea), a teleost species with genetic sex determination (GSD) and with undifferentiated sex chromosomes. We observed genomic homology and polymorphic segregation of the proto-sex locus between sexes. Expression of dmrt1 showed a stepwise increase in the development of testis, but not in the ovary. We infer that the inception of the proto-sex locus involves a few divergences in nucleotide sequences and slight suppression of recombination in an autosome region. In androgen-induced sex reversal of genetic females, in addition to dmrt1, genes in the conserved dmrt1 cluster, and the rest of the sex determination network were activated. We provided evidence that broad functional links were shared by genetic sex determination and environmental sex reversal.

evolutionary biology↗

bioRxiv2020

Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity

Microinfarcts are common among the elderly, and patients with microinfarcts are more vulnerable to another stroke. However, the potential effect of microinfarct on recurrent stroke remains elusive. In this study, we investigated the detrimental effect of microinfarct on recurrent stroke in mice. Microinfarct was induced using two-photon laser and photothrombotic stroke was induced in the cortex contralateral to microinfarct four weeks later. We found that CMI could trigger the formation of innate immune memory, which exacerbated the pro-inflammatory response and ischemic injury in second photothrombotic stroke. Furthermore, we clarified the role of NLRP3 inflammasome in the nuclei of microglia, which interacts with the MLL1 complex and thereby increases H3K4 methylation, suggesting that NLRP3 is critical in microinfarct-induced innate immune memory. Additionally, NLRP3 knockout in microglia attenuated microinfarct-induced detrimental effects on recurrent stroke. Our study highlights the detrimental effect of trained immunity on the recurrent stroke and reveals the important role of NLRP3 in mediating the formation of this memory, which may be a therapeutic target to mitigate recurrent strokes.

immunology↗

bioRxiv2020

Adaptive evolution of DNA methylation reshaped gene regulation in maize

DNA methylation is a ubiquitous chromatin feature -- in maize, more than 25% of cytosines in the genome are methylated. Recently, major progress has been made in describing the molecular mechanisms driving methylation, yet variation and evolution of the methylation landscape during maize domestication remain largely unknown. Here we leveraged whole-genome sequencing (WGS) and whole genome bisulfite sequencing (WGBS) on populations of modern maize, landrace, and teosinte (Zea mays ssp. parviglumis) to investigate the adaptive and phenotypic consequences of methylation variations in maize. By using a novel estimation approach, we inferred the methylome site frequency spectrum (mSFS) to estimate forward and backward epimutation rates and selection coefficients. We found weak evidence for direct selection on DNA methylation in any context, but thousands of differentially methylated regions (DMRs) were identified in population-wide that are correlated with recent selection. Further investigation revealed that DMRs are enriched in 5 untranslated regions, and that maize hypomethylated DMRs likely helped rewire distal gene regulation. For two trait-associated DMRs, vgt1-DMR and tb1-DMR, our HiChIP data indicated that the interactive loops between DMRs and respective downstream genes were present in B73, a modern maize line, but absent in teosinte. Functional analyses suggested that these DMRs likely served as cis-acting elements that modulated gene regulation after domestication. Our results enable a better understanding of the evolutionary forces acting on patterns of DNA methylation and suggest a role of methylation variation in adaptive evolution.

plant biology↗

bioRxiv2020

Schistosoma Japonicum infection in Treg-specific USP21 knock-out mice

USP21, an E3 de-ubiquitin enzyme playing vital roles in physiological activities, is important for Treg cells to maintain immune homeostasis and control immune tolerance. To understand its diverse functions and potential mechanism is essential for disease development. We, using the USP21 gene-conditional knock-out mice model of Schistosoma Japonicum infection, found more cercariae developed into adults, and more eggs deposited in the liver in KO mice. However, immunohistochemistry showed the degree and the area of egg granuloma and liver fibrosis were both reduced. This suggested knock-out USP21 did affect the immunoregulation between schistosomes and the host. In KO mice the content of IFN-gamma and IL-4, and the expression of anti-SEA IgG and anti-SWAP IgG both increased in the liver, spleen and blood by flow cytometry, while the content of IL-10, lL-17A, IL-23, IL-9 and the expression of USP21 and anti-SEA IgM decreased. This indicated USP21-knockout-Tregs promoted both Th1-type and Th2-type immunity and inhibited other immunities during schistosomes infection, which disordered the host immunity. This study revealed the immunomodulatory of USP21 and preliminarily suggests it might be essential to regulate the complex immune network between the host and schistosomes. USP21 provides a new possible target for schistosomiasis treatment in the future. Author summarySchistosomiasis is a common neglected tropical disease that affects more than 230 million people worldwide. Therefore, the study on the mechanism of immune interaction between schistosomas and the host is not only helpful for the understanding of immune homeostasis, but also helpful for the further development of the treatment of schistosomiasis. Ubiquitin Specific Protease 21(USP21) has been shown to be involved in the regulation of many biological processes, such as maintaining immune homeostasis and regulating cell growth. Here, we observed that the specific deletion of USP21 led to the decrease of mices ability to resist schistosomes infection and promoted the survival of schistosomes. It was also proved that unstable regulatory T cells would produce polarization phenomenon and promote differentiation to helper T cells, which would lead to disorder of immune response in mice. However, this process reduced the serious immune pathological damage caused by egg granuloma. Our findings reveal that USP21 may be an important molecule regulating immune interaction between Schistosoma japonicum and the host.

immunology↗