Biology subjects

Xue, Y.

Publications and source records attributed to Xue, Y..

At least 91 records · Page 5Linked to original sources

bioRxiv2023

The marine natural microbiome mediates physiological outcomes in host nematodes

Nematodes are the most abundant metazoans in marine sediments, many of which are bacterivores, however how habitat bacteria effects physiological outcomes in marine nematodes remains largely unknown. Here, we used a Litoditis marina inbred line to assess how native bacteria modulates host nematode physiology. We characterized seasonal dynamic bacterial compositions in L. marina habitats, and examined the impacts of 448 habitat bacteria isolates on L. marina development, then focused on HQbiome with 73 native bacteria, of which we generated 72 whole genomes sequences. Unexpectedly, we found that the effects of marine native bacteria on the development of L. marina and its terrestrial relative Caenorhabditis elegans were significantly positively correlated. Next, we reconstructed bacterial metabolic networks and identified several bacterial metabolic pathways positively correlated with L. marina development (e.g., ubiquinol and heme b biosynthesis), while pyridoxal 5-phosphate biosynthesis pathway was negatively associated. Through single metabolite supplementation, we verified CoQ10, heme b, Acetyl-CoA, and acetaldehyde promoted L. marina development, while vitamin B6 attenuated growth. Notably, we found that only four development correlated metabolic pathways were shared between L. marina and C. elegans. Furthermore, we identified two bacterial metabolic pathways correlated with L. marina lifespan, while a distinct one in C. elegans. Strikingly, we found that glycerol supplementation significantly extended L. marina but not C. elegans longevity. Moreover, we comparatively demonstrated the distinct gut microbiota characteristics and their effects on L. marina and C. elegans physiology. Our integrative approach will provide a microbe-nematodes framework for microbiome mediated effects on host animal fitness.

microbiology↗

bioRxiv2023

A SREBF2-dependent gene program drives an immunotolerant dendritic cell population during cancer progression

Dendritic cells (cDCs) are essential mediators of anti-tumor immunity. Cancers have developed mechanisms to render DCs dysfunctional within the tumor microenvironment. Utilizing CD63 as a unique surface marker, we demonstrate that mature regulatory DCs (mregDCs) suppress DC antigen cross-presentation while driving TH2 and regulatory T cell differentiation within tumor-draining lymph node tissues. Transcriptional and metabolic studies show that mregDC functionality is dependent upon the mevalonate biosynthetic pathway and the master transcription factor, SREBP2. Melanoma-derived lactate activates DC SREBP2 in the tumor microenvironment (TME) and drives mregDC development from conventional DCs. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promotes anti-tumor CD8+ T cell activation and suppresses melanoma progression. CD63+ mregDCs reside within the sentinel lymph nodes of melanoma patients. Collectively, this work describes a tumor-driven SREBP2-dependent program that promotes CD63+ mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME. One Sentence SummaryThe metabolic transcription factor, SREBF2, regulates the development and tolerogenic function of the mregDC population within the tumor microenvironment.

immunology↗

bioRxiv2023

In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1-mutant lung cancer

LKB1/STK11 is a serine/threonine kinase that plays a major role in controlling cell metabolism, resulting in potential therapeutic vulnerabilities in LKB1-mutant cancers. Here, we identify the NAD+ degrading ectoenzyme, CD38, as a new target in LKB1-mutant NSCLC. Metabolic profiling of genetically engineered mouse models (GEMMs) revealed that LKB1 mutant lung cancers have a striking increase in ADP-ribose, a breakdown product of the critical redox co-factor, NAD+. Surprisingly, compared with other genetic subsets, murine and human LKB1-mutant NSCLC show marked overexpression of the NAD+-catabolizing ectoenzyme, CD38 on the surface of tumor cells. Loss of LKB1 or inactivation of Salt-Inducible Kinases (SIKs)--key downstream effectors of LKB1-- induces CD38 transcription induction via a CREB binding site in the CD38 promoter. Treatment with the FDA-approved anti-CD38 antibody, daratumumab, inhibited growth of LKB1-mutant NSCLC xenografts. Together, these results reveal CD38 as a promising therapeutic target in patients with LKB1 mutant lung cancer. SIGNIFICANCELoss-of-function mutations in the LKB1 tumor suppressor of lung adenocarcinoma patients and are associated with resistance to current treatments. Our study identified CD38 as a potential therapeutic target that is highly overexpressed in this specific subtype of cancer, associated with a shift in NAD homeostasis.

cancer biology↗

bioRxiv2023

Machine learning detection of SARS-CoV-2 high-risk variants

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved many high-risk variants, resulting in repeated COVID-19 waves of pandemic during the past years. Therefore, accurate early-warning of high-risk variants is vital for epidemic prevention and control. Here we construct a machine learning model to predict high-risk variants of SARS-CoV-2 by LightGBM algorithm based on several important haplotype network features. As demonstrated on a series of different retrospective testing datasets, our model achieves accurate prediction of all variants of concern (VOC) and most variants of interest (AUC=0.96). Prediction based on the latest sequences shows that the newly emerging lineage BA.5 has the highest risk score and spreads rapidly to become a major epidemic lineage in multiple countries, suggesting that BA.5 bears great potential to be a VOC. In sum, our machine learning model is capable to early predict high-risk variants soon after their emergence, thus greatly improving public health preparedness against the evolving virus.

bioinformatics↗

bioRxiv2023

Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages

The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previously suggested that an insufficient mucosal IgA response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot sufficiently boost the mucosal sIgA response in uninfected individuals, particularly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric and secretory IgA1 antibodies derived from four neutralizing IgG monoclonal antibodies targeting the receptor-binding domain of the spike protein (01A05, rmAb23, DXP-604 and XG014). Compared to their parental IgG antibodies, dimeric and secretory IgA1 antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgA1 form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2 and BA.4/5 with a 50-150-fold increase in potency, reaching the level of the most potent monoclonal antibodies described till date. In hACE2 transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Conversion of IgA and dimerization further enhanced or restored the neutralizing ability against the emerging Omicron sub-variants (DXP-604 for BQ.1, BQ.1.1 and BA2.75; 01A05 for BA2.75, BA.2.75.2 and XBB.1). Thus, dimeric or secretory IgA delivered by nasal administration may potentially be exploited for the treatment and prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by subvariants and, potentially, future VOCs. One Sentence SummaryEngineered dimeric and secretory IgA1 neutralized Omicron variant with higher potency than parental IgG.

microbiology↗

bioRxiv2023

Genetic control of cell layer interactions in plants via tissue mechanics

Plant development depends on coordination of growth between different cell layers. Coordination may be mediated by molecular signalling or mechanical connectivity between cells, but evidence for genetic control via direct mechanics has been lacking. We show that a brassinosteroid-deficient dwarf mutant of the aquatic plant Utricularia gibba has twisted internal tissue, likely caused by a mechanical constraint from a slow-growing epidermis creating tissue stresses. This conclusion is supported by showing that inhibition of brassinosteroid action in an Arabidopsis mutant compromised for cell adhesion, enhances epidermal crack formation, an indicator of increased tissue tension. Thus, genes driving brassinosteroid synthesis can promote growth of internal tissue by reducing mechanical epidermal constraint, showing that tissue mechanics plays a key role in coordinating growth between cell layers. One-Sentence SummaryInternal twists in a mutant carnivorous plant reveal how genes control growth via tissue mechanics.

plant biology↗

bioRxiv2022

Ghost admixture in eastern gorillas

Archaic admixture has had a significant impact on human evolution with multiple events across different clades, including from extinct hominins such as Neanderthals and Denisovans into modern humans. Within the great apes archaic admixture has been identified in chimpanzees and bonobos, but the possibility of such events has not been explored in other species. Here, we address this question using high-coverage whole genome sequences from all four extant gorilla subspecies, including six newly sequenced eastern gorillas from previously unsampled geographic regions. Using Approximate Bayesian Computation (ABC) with neural networks to model the demographic history of gorillas, we find a signature of admixture from an archaic ghost lineage into the common ancestor of eastern gorillas, but not western gorillas. We infer that up to 3% of the genome of these individuals is introgressed from an archaic lineage that diverged more than 3 million years ago from the common ancestor of all extant gorillas. This introgression event took place before the split of mountain and eastern lowland gorillas, likely more than 40 thousand years ago, and may have influenced perception of bitter taste in eastern gorillas. When comparing the introgression landscapes of gorillas, humans and bonobos, we find a consistent depletion of introgressed fragments on the X chromosome across these species. However, depletion in protein-coding content is not detectable in eastern gorillas, possibly as a consequence of stronger genetic drift in this species.

evolutionary biology↗

bioRxiv2022

Identification of a key genetic factor governing arabinan utilization in the gut microbiome suggests a novel therapeutic target for constipation

Probiotics have been widely used to improve impaired gastro-intestinal motility, yet their efficacy varied substantially across strains. Here, by a large-scale genetic screen plus in vivo measurements, we identified a key genetic factor (abfA cluster governing arabinan utilization) in probiotic Bifidobacterium longum harnessing the treatment efficacy against functional constipation (FC). Intriguingly, it also presents in a range of gut resident microbiota and played a protective role against FC. Next, our longitudinal multi-omics study in humans revealed that the exogenous abfA-cluster- carrying B. longum can well establish itself in the gut, and enrich arabinan-utilization residents and beneficial metabolites (e.g., acetate, butyrate, chenodeoxycholic acid and uracil). Finally, transplantation of abfA-cluster-enriched human microbiota to FC- induced germ-free mice recapitulated the marked gut-motility improvement and elevated production of beneficial metabolites. Collectively, our proof-of-concept study actively demonstrated a critical yet underexplored role of microbial abfA cluster in ameliorating FC, establishing generalizable principles for developing functional-genomics-directed probiotic therapies.

microbiology↗

bioRxiv2022

MORC proteins regulate transcription factor binding by mediating chromatin compaction in active chromatin regions

BackgroundThe Microrchidia (MORC) proteins are a family of evolutionarily conserved GHKL-type ATPases involved in chromatin compaction and gene silencing. Arabidopsis MORC proteins act in the RNA-directed DNA methylation (RdDM) pathway, where they act as molecular tethers to ensure the efficient establishment of RdDM and de novo gene silencing. However, MORC proteins also have RdDM-independent functions; although, their underlying mechanisms are unknown. ResultsIn this study, we examined regions of MORC binding where RdDM does not occur in order to shed light on the RdDM-independent functions of MORC proteins. We found that MORC proteins compact chromatin and reduce DNA accessibility to transcription factors (TFs), thereby repressing gene expression. We also found that MORC-mediated repression of gene expression was particularly important under conditions of stress. We showed that MORC proteins regulate TFs through either direct or indirect interactions, and these TFs can in some cases regulate their own transcription, resulting in feedforward loops. ConclusionsOur findings provide insights into the molecular mechanisms of MORC-mediated chromatin compaction and transcription regulation.

plant biology↗

bioRxiv2022

Transposable elements orchestrate subgenome-convergent and -divergent transcription in common wheat

The success of common wheat as the global staple crop is derived from genome diversity and redundancy as a result of allopolyploidization [1-3], giving rise to the major question how the divergent and convergent transcription among different subgenomes are achieved and harmonized in a single cell. The regulatory information is largely encoded in DNA regulatory elements (REs) interpreted by sequence specific transcription factors (TFs). Here, we created a catalog of genome-wide TF-binding sites (TFBS) to assemble an extensive wheat regulatory network comprising connections among 189 TFs and 3,714,431 REs, which enhances the understanding of wheat regulatory mechanisms on an unprecedented scale. A significant fraction of subgenome-divergent TFBS are derived from recent subgenome-asymmetric expansion of particular transposable element (TE) families. In contrary, TFBS derived from ancient TE expansion largely underwent parallel purifying selection during independent evolution of each subgenome, despite extensive unbalanced turnover of flanking TEs. Altogether, the subgenome-convergent and -divergent regulation in common wheat is orchestrated via differential evolutionary selection on paleo- and neo-TEs.

bioinformatics↗

bioRxiv2022

Single-nucleus RNA-seq reveals that MBD5, MBD6, and SILENZIO maintain silencing during epigenetic reprogramming in pollen

Silencing of transposable elements (TEs) drove the evolution of numerous redundant mechanisms of transcriptional regulation. Arabidopsis MBD5, MBD6, and SILENZIO act as TE repressors downstream of DNA methylation. Here we show via single-nucleus RNA-seq of developing male gametophytes that these repressors are critical for TE silencing in the pollen vegetative cell, which undergoes epigenetic reprogramming causing chromatin decompaction to support fertilization by sperm cells. Instead, other silencing mutants (met1, ddm1, mom1, morc) show loss of silencing in all pollen nucleus types and somatic cells. We found that TEs repressed by MBD5/6 gain accessibility in wild-type vegetative nuclei despite remaining silent, suggesting that loss of DNA compaction makes them sensitive to loss of MBD5/6. Consistently, crossing mbd5/6 to histone 1 mutants, which have decondensed chromatin in leaves, reveals derepression of MBD5/6-dependent TEs in leaves. MBD5/6 and SILENZIO thus act as a silencing system especially important when chromatin compaction is compromised.

molecular biology↗

bioRxiv2022

Histone chaperone ASF1 mediates H3.3-H4 deposition in Arabidopsis

Histone chaperones and chromatin remodelers control nucleosome dynamics, which are essential for transcription, replication, and DNA repair. The histone chaperone Anti-Silencing Factor 1 (ASF1) plays a central role in facilitating CAF-1-mediated replication-dependent H3.1 deposition and HIRA-mediated replication-independent H3.3 deposition in yeast and metazoans. Whether ASF1 function is evolutionarily conserved in plants is unknown. Here, we show that Arabidopsis ASF1 proteins display a preference for the HIRA complex. Simultaneous mutation of both Arabidopsis ASF1 genes caused a decrease in chromatin density and ectopic H3.1 occupancy at loci typically enriched with H3.3. Genetic, transcriptomic, and proteomic data indicate that ASF1 proteins strongly prefers the HIRA complex over CAF-1. asf1 mutants also displayed an increase in spurious Pol II transcriptional initiation and showed defects in the maintenance of gene body CG DNA methylation and in the distribution of histone modifications. Furthermore, ectopic targeting of ASF1 caused excessive histone deposition, less accessible chromatin, and gene silencing. These findings reveal the importance of ASF1-mediated histone deposition for proper epigenetic regulation of the genome.

plant biology↗

bioRxiv2022

A 4-bp natural deletion of maize Na+/H+ exchanger gene alters maize salt stress tolerance

Soil salinity is a major environmental constraint severely reducing plant growth and crop productivity worldwide. Knowledge of salt tolerance-related genes can facilitate improving crop salt tolerance and alleviating the threat of increasing saline area to world food security. Here, we identified a major locus SALT TOLERANCE 1 (qST1) conferring maize salt tolerance via bulked segregant RNA-Seq (BSR-Seq). qST1 encodes a plasma membrane Na+/H+ exchanger ZmSOS1 which is the ortholog of Arabidopsis thaliana SOS1 gene. In salt-sensitive variety D9H, the natural variation of 4-bp deletion in the coding sequence of ZmSOS1 gene was the causal allele for salt sensitivity. We identified two ethyl methanesulfonate-induced mutants, zmsos1-1 and zmsos1-2, which were sensitive to salt stress and cant complement salt-sensitive variety under salt stress within an allelism test. Overexpression of ZmSOS1 enhanced maize seedling salt tolerance. ZmSOS1 can increase the salt tolerance of Arabidopsis sos1-1 mutant and can be activated by AtSOS2 and AtSOS3 in yeast cells, suggesting that ZmSOS1 confers salt tolerance through the conserved SOS signaling pathway in maize. The detrimental allele harboring the 4-bp deletion was rarely found in the natural population but appeared in an important heterotic group composed of x1132x-derived inbred lines which have been used widely for breeding dozens of hybrid varieties in China. The 4-bp deletion-based molecular marker has been successfully used to improve salt-sensitive varieties in a backcross and marker-assisted breeding program by screening and purging this deleterious allele.

plant biology↗

bioRxiv2022

CRIC-seq reveals positional rule of PTBP1-mediated long-range RNA looping in splicing regulation

RNA-binding proteins bind at different positions of pre-mRNA molecules to promote or reduce the usage of a particular exon. Seeking to understand the working principle of these positional effects, we develop a CRIC-seq method to enrich single RBP-mediated in situ RNA-RNA spatial interacting fragments for deep sequencing. We determine hnRNPA1- and PTBP1-mediated RNA-RNA interactions and regulatory mechanisms in HeLa cells. Unexpectedly, 3D RNA map analysis shows that PTBP1-mediated loops in introns preferably promote cassette exon splicing by accelerating asymmetric intron removal, whereas the loops spanning across cassette exon primarily repress splicing. This "positional rule" can faithfully predict PTBP1-regulated splicing outcomes. We further demonstrate that cancer-related splicing quantitative trait loci can disrupt RNA loops by reducing PTBP1 binding on pre-mRNAs to cause aberrant splicing in tumors. Our study presents a powerful method for exploring the functions of RBP-mediated RNA-RNA interactions in gene regulation and disease.

molecular biology↗

bioRxiv2022

Nuclear m6A Reader YTHDC1 Promotes Muscle Stem Cell Activation/Proliferation by Regulating mRNA Splicing and Nuclear Export

Skeletal muscle stem cells (also known as satellite cells, SCs) are essential for muscle regeneration and the regenerative activities of SCs are intrinsically governed by gene regulatory mechanisms but the post-transcriptional regulation in SCs remains largely unknown. N(6)-methyladenosine (m6A) modification of RNAs is the most pervasive and highly conserved RNA modification in eukaryotic cells and exerts powerful impact on almost all aspects of mRNA processing which is mainly endowed by its binding with m6A reader proteins. Here in this study, we investigate the previously uncharacterized regulatory roles of YTHDC1, a m6A reader in SCs. Our results demonstrate YTHDC1 is an essential regulator of SC activation and proliferation upon acute injury induced muscle regeneration. The induction of YTHDC1 is indispensable for SC activation and proliferation thus inducible YTHDC1 depletion almost abolishes SC regenerative capacity. Mechanistically, transcriptome-wide profiling using LACE-seq in both SCs and C2C12 myoblasts identifies m6A mediated binding targets of YTHDC1. Next, splicing analysis defines splicing mRNA targets of m6A-YTHDC1. Furthermore, nuclear export analysis also leads to identification of potential mRNA export targets of m6A-YTHDC1 in SCs and C2C12 myoblasts and interestingly some mRNAs can be regulated at both splicing and export levels. Lastly, we map YTHDC1 interacting protein partners in myoblasts and unveil a myriad of factors governing mRNA splicing, nuclear export and transcription, among which hnRNPG appears to be a bona fide interacting partner of YTHDC1. Altogether, our findings uncover YTHDC1 as an essential factor controlling SC regenerative ability through multi-faceted gene regulatory mechanisms in myoblast cells.

molecular biology↗

bioRxiv2022

Characterization of network hierarchy reflects cell-state specificity in genome organization

Dynamic chromatin structure acts as the regulator of transcription program in crucial processes including cancer and cell development, but a unified framework for characterizing chromatin structural evolution remains to be established. Here, we performed graph inferences on Hi-C datasets and derived the chromatin contact networks (CCNs). We discovered significant decreases in information transmission efficiencies in CCNs of colorectal cancer (CRC) and T-lineage acute lymphoblastic leukemia (T-ALL) compared to corresponding normal controls through graph statistics. Through network embedding in Poincare disk, the hierarchy depths of CCNs from CRC and T-ALL patients were found to be significantly shallower compared to their normal controls. A reverse trend of CCN change was observed for the transition from embryo to differentiated primary tissues. During early embryo developments of both human and mouse, the hierarchy of embedded chromatin structure gradually establishes. Additionally, we found tissue-specific conservation of hierarchy order in normal CCNs, which was disturbed in tumor. Our findings uncover the cell-state related hierarchical characteristics in chromatin structure, which reveal chromatin loci that play important roles in stabilizing the cellular conditions.

bioinformatics↗

bioRxiv2022

EDoF-Miniscope: pupil engineering for extended depth-of-field imaging in a fluorescence miniscope

Extended depth of field (EDoF) microscopy has emerged as a powerful solution to greatly increase the access into neuronal populations in table-top imaging platforms. Here, we present EDoF-Miniscope, which integrates an optimized thin and lightweight binary diffractive optical element (DOE) onto the gradient refractive index (GRIN) lens of a head-mounted fluorescence miniature microscope, i.e. "miniscope". We achieve an alignment accuracy of 70 m to allow a 2.8X depth-of-field extension between the twin foci. We optimize the phase profile across the whole back aperture through a genetic algorithm that considers the primary GRIN lens aberrations, optical property of the submersion media, and axial intensity loss from tissue scattering in a Fourier optics forward model. Compared to other computational miniscopes, our EDoF-Miniscope produces high-contrast signals that can be recovered by a simple algorithm and can successfully capture volumetrically distributed neuronal signals without significantly compromising the speed, signal-to-noise, signal-to-background, and maintain a comparable 0.9-m lateral spatial resolution and the size and weight of the miniature platform. We demonstrate the robustness of EDoF-Miniscope against scattering by characterizing its performance in 5-m and 10-m beads embedded in scattering phantoms. We demonstrate that EDoF-Miniscope facilitates deeper interrogations of neuronal populations in a 100-m thick mouse brain sample, as well as vessels in a mouse brain. Built from off-the-shelf components augmented by a customizable DOE, we expect that this low-cost EDoF-Miniscope may find utility in a wide range of neural recording applications.

bioengineering↗

bioRxiv2022

McAN: an ultrafast haplotype network construction algorithm

SummaryHaplotype network is becoming popular due to its increasing use in analyzing genealogical relationships of closely related genomes. We newly proposed McAN, a minimum-cost arborescence based haplotype network construction algorithm, by considering mutation spectrum history (mutations in ancestry haplotype should be contained in descendant haplotype), node size (corresponding to sample count for a given node) and sampling time. McAN is two orders of magnitude faster than the state-of-the-art algorithms, making it suitable for analyzation of massive sequences. AvailabilitySource code is written in C/C++ and available at https://github.com/Theory-Lun/McAN and https://ngdc.cncb.ac.cn/biocode/tools/BT007301 under the MIT license. The online web service of McAN is available at https://ngdc.cncb.ac.cn/ncov/online/tool/haplotype. SARS-CoV-2 dataset are available at https://ngdc.cncb.ac.cn/ncov/.

bioinformatics↗