Biology subjects

Yang, Y.

Publications and source records attributed to Yang, Y..

At least 991 records · Page 55Linked to original sources

bioRxiv2022

Orchestration of Chlorophyll and Carotenoid Biosynthesis by ORANGE Family Proteins in Plant

Chlorophyll and carotenoid are essential photosynthetic pigments. Plants must spatiotemporally coordinate the needs of chlorophyll and carotenoid for optimal photosynthesis and plant fitness in response to diverse environmental and developmental cues. However, how these two biosynthesis pathways are orchestrated remains largely unknown. Here, we report that the highly conserved ORANGE (OR) family proteins are the common regulators of both pathways via posttranslationally regulating the first committed enzyme in each pathway. We demonstrate that OR family proteins physically interact with magnesium chelatase subunit I (CHLI) in addition to phytoene synthase (PSY) and concurrently regulate CHLI and PSY protein stability and activity. We show that loss of OR genes hinders both chlorophyll and carotenoid biosynthesis, limits light-harvesting complex assembly, and impairs thylakoid grana stacking in chloroplast. OR overexpression safeguards photosynthetic pigment biosynthesis and enhances thermotolerance in both Arabidopsis and tomato plants. Our findings establish a conserved mechanism of green plant to coordinate chlorophyll and carotenoid biosynthesis and provide a potential genetic target to generate climate-resilient crops.

plant biology↗

bioRxiv2022

Generative pretraining from large-scale transcriptomes: Implications for single-cell deciphering and clinical translation

Exponential accumulation of single-cell transcriptomes poses great challenge for efficient assimilation. Here, we present an approach entitled tGPT towards integration of 22.3 million single-cell transcriptomes by modeling gene expression rankings as generative pretraining task. tGPT is conceptually simple in that it autoregressively models the ranking of a gene in the context of its preceding neighbors. We demonstrated the high performance of tGPT on a range of fundamental single-cell analysis tasks and novel applications on bulk tissues. The single-cell clusters and cell lineage trajectories derived from tGPT are highly aligned with known cell labels and states. The feature patterns of tumor bulk tissues learned by tGPT are associated with a wide range of genomic alteration events, prognosis and treatment outcome of immunotherapy. tGPT represents a new analytical paradigm for integrating and deciphering massive amount of transcriptome data and it will facilitate the interpretation and clinical translation of single-cell transcriptomes.

bioinformatics↗

bioRxiv2022

Observing noncovalent interactions in experimental electron density for macromolecular systems: A novel perspective for protein-ligand interaction research

We report for the first time the use of experimental electron density (ED) in the Protein Data Bank for modeling non-covalent interactions (NCIs) for protein-ligand complexes. Our methodology is based on the reduced electron density gradient (RDG) theory describing intermolecular NCI by ED and its first derivative. We established a database called the Experimental NCI Database (ExptNCI; http://ncidatabase.stonewise.cn/#/nci) containing ED saddle points, indicating ~200,000 NCIs from over 12,000 protein-ligand complexes. We also demonstrated the use of the database for depicting amide-{pi} interactions in a protein-ligand binding system. In summary, the database provides details on experimentally observed NCIs for protein-ligand complexes and can support future studies, including studies on rarely documented NCIs and the development of artificial intelligent models for protein-ligand binding prediction.

biochemistry↗

bioRxiv2022

Proteostasis is differentially modulated by inhibition of translation initiation or elongation

Recent work has revealed an increasingly important role for mRNA translation in maintaining proteostasis. Inhibiting translation protects from various proteostatic insults, including heat, expression of aggregation-prone proteins, or aging. However, multiple studies have come to differing conclusions about the mechanisms underlying the protective effects of translation inhibition. Here, we systematically lower translation either by pharmacologically inhibiting translation initiation or elongation and show that each step activates distinct protective responses in Caenorhabditis elegans. Targeting initiation triggers an HSF-1 dependent mechanism that protects from heat and age-associated protein misfolding but not from proteotoxicity caused by proteasome dysfunction. Conversely, targeting elongation triggers an HSF-1 independent mechanism that protects from heat and proteasome dysfunction but not from age-associated protein aggregation. Furthermore, while inhibiting translation initiation increases lifespan in wild-type worms, inhibiting translation elongation only extends lifespan when the animals exhibit preexisting proteotoxic stress--either as a result of aggregation-prone protein expression or hsf-1 deficiency. Together our findings suggest that organisms evolved complementary mechanisms that the mRNA translation machinery can trigger to restore proteostasis.

biochemistry↗

bioRxiv2022

Chromatin reprogramming and transcriptional regulation orchestrate embryogenesis in hexaploid wheat

Embryogenesis represents the beginning of life cycle, but our understanding of the regulatory circuitry in plants is far lagged to animals. Here, we draw a transcriptome trajectory and chromatin landscape profile during embryogenesis of most cultivated crop hexaploid wheat, highlighting large-scale chromatin reconfiguration and distinct proximal and distal transcriptional regulation in defining cell fate transition. Upon fertilization, H3K27ac and H3K4me3 resetting were correlated with maternal genome silence, while de novo building of chromatin accessibility activated zygotic genome. Global depletion of H3K27me3 in pre-embryo results in a permissive chromatin environment with gain-of-chromatin accessibility, allowing subsequent hierarchical cis- and trans-regulation network mediated by key factors, such as LEC1, MYB, ZHD, LEC2, governing embryo pattern formation. By contrast, H3K27me3 restoration coordinating with chromatin compaction in developmental genes attenuated totipotency and prohibited extensive organogenesis during embryo maturation. In addition, dynamic biased expression of homeolog triads and diverse expression profiles after polyploidization were observed. This is correlated with asymmetric transposon elements insertion in accessible proximal and distal regions. Thus, our study revealed a plant-specific chromatin reprogramming process in facilitating the hierarchical transcription regulation circuits mediated "inverse hourglass model" and unveiled epigenetic regulation of evolutionary divergence among different sub-genome in shaping embryogenesis in polyploidy wheat.

plant biology↗

bioRxiv2022

A Multisite and Multimodal Comparative Study of Cerebellar Connectome Between Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorders

The cerebellum has been increasingly recognized to play key roles in the pathology of multiple sclerosis (MS) and spectrum disorders (NMOSD), two main demyelinating diseases with similar clinical presentations. Despite accumulating evidence from neuroimaging research for cerebellar volumetric alterations in the diseases, however, there have been no network-based studies examining convergent and divergent alterations in cerebellar connectome between MS and NMOSD. This multisite and multimodal study examined common and specific alterations in within-cerebellar coordination and cerebello-cerebral communication between MS and NMOSD by retrospectively collecting structural and resting-state functional MRI data from 208 MS patients, 200 NMOSD patients and 228 healthy controls (HCs) in seven sites in China. Morphological brain networks were constructed by estimating interregional similarity in cortical thickness and functional brain networks were formed by calculating interregional temporal synchronization in functional signals. After identifying cerebellar modular architecture and based on prior cerebral cytoarchitectonic classification and functional partition, within-cerebellar and cerebello-cerebral morphological and functional connectivity were compared among the MS, NMOSD and HC groups. Five modules were identified within the cerebellum including Primary Motor A (PMA), Primary Motor B (PMB), Primary Non-Motor (PNM), Secondary Motor (SM) and Secondary Non-Motor (SNM) modules. Compared with the HCs, the MS and NMOSD patients exhibited both increases and decreases in within-cerebellar morphological connectivity that were mainly involved in the PMA, PMB and SNM. Particularly, the two patient groups showed a common altered pattern characterized by decreases between the PMA and SNM, both of which were more densely connected with the PMB. For cerebello-cerebral morphological connectivity, widespread reductions were found in both patient groups for the SM and SNM with almost all cerebral cytoarchitectonic classes and functional systems while increases were observed only in the NMOSD patients for the PMB with cerebral areas involving motor and sensory domains. With regard to cerebellar functional connectivity, fewer alterations were observed in the patients that were all characterized by reductions and were mainly involved in cerebello-cerebral interactions between cerebellar motor modules and cerebral association cortex and high-order networks, particularly in the NMOSD patients. Cerebellar connectivity-based classification achieved around 60% accuracies to distinguish the three groups to each other with morphological connectivity as predominant features for differentiating the patients from controls while functional connectivity for discriminating the two diseases. Altogether, this study characterizes common and specific circuit dysfunctions of the cerebellum between MS and NMOSD, which provide novel insights into shared and unique pathophysiologic mechanisms underlying the two diseases.

neuroscience↗

bioRxiv2022

A local translation program regulates centriole amplification in the airway epithelium

Biogenesis of organelles requires targeting of a subset of proteins to specific subcellular domains by signal peptides or mechanisms controlling mRNA localization and local translation. How local distribution and translation of specific mRNAs for organelle biogenesis is achieved remains elusive and likely to be dependent on the cellular context. Here we identify Trinucleotide repeat containing-6a (Tnrc6a), a component of the miRNA pathway, distinctively localized to apical granules of differentiating airway multiciliated cells (MCCs) adjacent to centrioles. In spite of being enriched in TNRC6A and the miRNA-binding protein AGO2, they lack enzymes for mRNA degradation. Instead, we found these apical granules enriched in components of the mRNA translation machinery and newly synthesized proteins suggesting that they are specific hubs for target mRNA localization and local translation in MCCs. Consistent with this, Tnrc6a loss of function prevented formation of these granules and led to a broad reduction, rather than stabilization of miRNA targets. These included downregulation of key genes involved in ciliogenesis and was associated with defective multicilia formation both in vivo and in primary airway epithelial cultures. Similar analysis of Tnrc6a disruption in yolk sac showed stabilization of miRNA targets, highlighting the potential diversity of these mechanisms across organs. HighlightsO_LITnrc6a is expressed in the lung selectively in differentiating multiciliated cells (MCC) adjacent to centrioles. C_LIO_LITNRC6A localizes to apical granules containing AGO2, miRNAs and their targets, but lacking mRNA degradation enzymes. C_LIO_LITNRC6A granules are enriched in components of the mRNA translation machinery and show evidence of concentrated newly-synthesized proteins C_LIO_LILoss of Tnrc6a in the lung leads to reduction, not stabilization of miRNA targets. C_LIO_LITnrc6a is required for efficient centriole amplification and multicilia formation. C_LI

cell biology↗

bioRxiv2022

GhCO and GhCRY1 accelerate floral meristem initiation in response to blue light to shorten cotton breeding

The shoot apical meristem (SAM) is a special category of tissue with pluripotency that forms new organs and individuals, especially floral individuals. However, little is known about the fate of cotton SAMs as a tunica corpus structure. Here, we demonstrate that cotton SAM fate decisions depend on light signals and circadian rhythms, and the genes GhFKF1, GhGI, GhCRY1 and GhCO were responsible for SAM fate decisions and highlighted via RNA sequencing (RNA-seq) analysis of different cotton cultivars, as confirmed by genetic analysis via the CRISPR-Cas9 system. In situ hybridization (ISH) analysis showed that the GhCO gene, induced by a relatively high blue light proportion, was highly upregulated during the initiation of floral meristems (FMs). Further blue light treatment analysis showed that the transition from vegetative to reproductive growth of SAM was promoted by a high proportion of blue light, coupled with high expression of the blue light-responsive genes GhCO and GhCRY1. Taken together, our study suggests that blue light signalling plays a key role in the fate decision of cotton SAM. These results provide a strategy to regulate the SAM differentiation of cotton by using the CRISPR-Cas9 system to change the ratio of red and blue light absorption to breed early-maturity cotton. One-sentence summaryThe SAM differentiation especially the initiation of floral meristem of upland cotton were mediated by genes GhCO and GhCRY1 which in response to blue light.

developmental biology↗

bioRxiv2022

Chronic Ca2+ imaging of cortical neurons with long-term expression of GCaMP-X

Dynamic Ca2+ signals reflect acute changes in membrane excitability (e.g. sensory response), and also mediate intracellular signaling cascades normally of longer time scales (e.g., Ca2+-dependent neuritogenesis). In both cases, chronic Ca2+ imaging has been often desired, but largely hindered by unexpected cytotoxicity intrinsic to GCaMP, a popular series of genetically-encoded Ca2+ indicators. Here, we demonstrate that the recently developed GCaMP-X outperforms GCaMP in long-term probe expression and/or chronic Ca2+ imaging. GCaMP-X shows much improved compatibility with neurons and thus more reliable than GCaMP as demonstrated in vivo by acute Ca2+ responses to whisker deflection or spontaneous Ca2+ fluctuations over an extended time frame. Chronic Ca2+ imaging data ([≥]1 month) are acquired from the same set of cultured cortical neurons, unveiling that spontaneous/local Ca2+ activities would progressively develop into autonomous/global Ca2+ oscillations. Besides the morphological indices of neurite length or soma size, the major metrics of oscillatory Ca2+, including rate, amplitude, synchrony among different neurons or organelles have also been examined along with the developmental stages. Both neuritogenesis and Ca2+ signals are dysregulated by GCaMP in virus-infected or transgenic neurons, in direct contrast to GCaMP-X without any noticeable side-effect. Such in vitro data altogether consolidate the unique importance of oscillatory Ca2+ to activity-dependent neuritogenesis, as one major factor responsible for the distinctions between GCaMP vs GCaMP-X in vivo. For the first time with GCaMP-X of long-term expression in neurons, spontaneous and sensory-evoked Ca2+ activities are imaged and evaluated both in vitro and in vivo, providing new opportunities to monitor neural development or other chronic processes concurrently with Ca2+ dynamics.

neuroscience↗

bioRxiv2022

Putative host-derived insertions in the genome of circulating SARS-CoV-2 variants

Insertions in the SARS-CoV-2 genome have the potential to drive viral evolution, but the source of the insertions is often unknown. Recent proposals have suggested that human RNAs could be a source of some insertions, but the small size of many insertions makes this difficult to confirm. Through an analysis of available direct RNA sequencing data from SARS-CoV-2 infected cells, we show that viral-host chimeric RNAs are formed through what are likely stochastic RNA-dependent RNA polymerase template switching events. Through an analysis of the publicly available GISAID SARS-CoV-2 genome collection, we identified two genomic insertions in circulating SARS-CoV-2 variants that are identical to regions of the human 18S and 28S rRNAs. These results provide direct evidence of the formation of viral-host chimeric sequences and the integration of host genetic material into the SARS-CoV-2 genome, highlighting the potential importance of host-derived insertions in viral evolution. IMPORTANCEThroughout the COVID-19 pandemic, the sequencing of SARS-CoV-2 genomes has revealed the presence of insertions in multiple globally circulating lineages of SARS-CoV-2, including the Omicron variant. The human genome has been suggested to be the source of some of the larger insertions, but evidence for this kind of event occurring is still lacking. Here, we leverage direct RNA sequencing data and SARS-CoV-2 genomes to show host-viral chimeric RNAs are generated in infected cells and two large genomic insertions have likely been formed through the incorporation of host rRNA fragments into the SARS-CoV-2 genome. These host-derived insertions may increase the genetic diversity of SARS-CoV-2 and expand its strategies to acquire genetic materials, potentially enhancing its adaptability, virulence, and spread.

bioinformatics↗

bioRxiv2022

GFAP: ultra-fast and accurate gene functional annotation software for plants

Sequence alignment is the basis of gene functional annotation for unknow sequences. Selecting closely related species as the reference species should be an effective way to improve the accuracy of gene annotation for plants, compared with only based on one or some model plants. Therefore, limited species number in previous software or website is disadvantageous for plant gene annotation. Here, we collected the protein sequences of 236 plant species with known genomic information from 63 families. After that, these sequences were annotated by pfam, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases to construct our databases. Furthermore, we developed the software, Gene Annotation Software for Plants (GFAP), to perform gene annotation using our databases. GFAP, an open-source software running on Windows and MacOS systems, is an efficient and network independent tool. GFAP can search the protein domain, GO and KEGG information for 43000 genes within 4 minutes. In addition, GFAP can also perform the sequence alignment, statistical analysis and drawing. The website of https://gitee.com/simon198912167815/gfap-database provides the software, databases, testing data and video tutorials for users. GFAP contained large amount of plant-species information. We believe that it will become a powerful tool in gene annotation using closely related species for phytologists.

bioinformatics↗

bioRxiv2022

Three amphioxus reference genomes reveal gene and chromosome evolution of chordates

The slow-evolving invertebrate amphioxus has an irreplaceable role in advancing our understanding into the vertebrate origin and innovations. Here we resolve the nearly complete chromosomal genomes of three amphioxus species, one of which best recapitulates the 17 chordate ancestor linkage groups. We reconstruct the fusions, retention or rearrangements between descendants of whole genome duplications (WGDs), which gave rise to the extant microchromosomes likely existed in the vertebrate ancestor. Similar to vertebrates, the amphioxus genome gradually establishes its 3D chromatin architecture at the onset of zygotic activation, and forms two topologically associated domains at the Hox gene cluster. We find that all three amphioxus species have ZW sex chromosomes with little sequence differentiation, and their putative sex-determining regions are nonhomologous to each other. Our results illuminate the unappreciated interspecific diversity and developmental dynamics of amphioxus genomes, and provide high-quality references for understanding the mechanisms of chordate functional genome evolution.

evolutionary biology↗

bioRxiv2022

Phosphoantigens are Molecular Glues that Promote Butyrophilin 3A1/2A1 Association Leading to Vγ9Vδ2 T Cell Activation

Tumor cells and pathogen-infected cells are presented to human {gamma}{delta} T cells based on "inside-out" signaling in which metabolites called phosphoantigens (pAgs) inside target cells are recognized by the intracellular domain of a butyrophilin protein (BTN3A1), leading to an extracellular conformational change. Here, we report that pAgs function as molecular "glues" that initiate a heteromeric association between the intracellular domains of BTN3A1 and the structurally similar BTN2A1. Working with both exogenous and endogenous pAgs, we used x-ray crystallography, mutational studies, cellular assays, synthetic probe as well as molecular dynamics investigations to determine how pAgs glue intracellular BTN3A1 and BTN2A1 together for the "inside-out" signaling that triggers {gamma}{delta} T cell activation. This {gamma}{delta} T cell-specific mode of antigen sensing creates opportunities for the development of alternative immunotherapies against cancer and infectious diseases that do not involve {beta} T cells. One Sentence SummaryThe responses of gamma-delta T cells to cancer cells or pathogens are initiated via the intracellular association of heteromeric butyrophilins that are glued together by isoprenoid metabolites.

immunology↗

bioRxiv2022

Prelimbic proBDNF facilitates memory destabilization by regulation of neuronal function in juveniles

Fear regulation changes as a function of age and adolescence is a key developmental period for the continued maturation of fear neural circuitry. The involvement of prelimbic proBDNF in fear memory extinction and its mediated signaling were reported previously. Given the inherent high level of proBDNF during juvenile period, we tested whether prelimbic proBDNF regulated synaptic and neuronal functions allowing to influencing retrieval-dependent memory processing. By examining freezing behavior of auditory fear conditioned rats, we found high levels of prelimbic proBDNF in juvenile rats enhanced destabilization of the retrieval-dependent weak but not strong fear memory through activating p75NTR-GluN2B signaling. This modification was attributed to the increment in proportion of thin type spine and promotion in synaptic function, as evidence by facilitation of NMDA-mediated EPSCs and GluN2B-dependent synaptic depression. The strong prelimbic theta- and gamma-oscillation coupling predicted the suppressive effect of proBDNF on the recall of post-retrieval memory. Our results critically emphasize the importance of developmental proBDNF for modification of retrieval-dependent memory and provide a potential critical targeting to inhibit threaten memories associated with neurodevelopment disorders.

neuroscience↗

bioRxiv2022

Rsc3K, a SMV resistance gene localized on chromosome 2 in soybean cv. Kefeng No.1, interacts with virulence determinant P3

Soybean mosaic virus (SMV) is one of the most devastating viral pathogens in Glycine max (L.) Merr (soybean). Twenty-two SMV strains (SC1-SC22) isolated in China were identified based on their responses to ten soybean cultivars. By using the F2-derived F3 (F2:3) and recombinant inbred line (RIL) populations of resistant Soybean cultivar (cv.) Kefeng No.1 x susceptible cv. Nannong 1138-2, we localized the gene mediating resistant to SMV-SC3 strain to a 90 kb interval on chromosome 2 in Kefeng No.1. Bean pod mottle virus (BPMV)-induced gene silencing (VIGS) were used to study the gene function of candidate genes in the mapping interval and revealed that an recombinant gene, later named as Rsc3K, caused by internal deletion of a genomic DNA frag ement in Kefeng No.1, is the resistant gene to SMV-SC3. By shuffling genes between avirulent isolate SC3 and avirulent SMV isolate 1129, we found that P3 is the virulence determinant causing resistance on Kefeng No.1. We showed the interaction between Rsc3K and P3 by the yeast two-hybrid (Y2H) and bimolecular fluorescent complementation (BiFC) assays. In conclusion, this study demonstrated that Rsc3K plays a crucial role in resistance of Kefeng No.1 to SMV-SC3 by direct interaction with viral protein P3. HighlightRsc3K resistant to SMV-SC3 by interacting with P3.

molecular biology↗

bioRxiv2022

Parasite defensive limb movements enhance signal attraction in male little torrent frogs: insight into the evolution of multimodal signals

Many animals rely on complex sexual signals that target multiple senses to attract mates and repel rivals. These multimodal mating displays can however also attract unintended receivers, which can be an important driver of signal complexity. Despite being taxonomically widespread, we often lack insight into how multimodal signals evolve from unimodal signals and in particular what roles unintended eavesdroppers play. Here we assess whether the physical movements of parasite defense behavior increase the complexity and attractiveness of an acoustic sexual signal in the little torrent frog (Amolops torrentis). Calling males of this species often display limb movements in order to defend against blood-sucking parasites such as frog-biting midges that eavesdrop on their acoustic signal. Through mate choice tests we show that some of these midge-evoked movements influence female preference for acoustic signals. Our data suggest that midge-induced movements may be incorporated into a sexual display, targeting both hearing and vision in the intended receiver. Females may play an important role in incorporating these multiple components because they prefer signals which combine multiple programs. Our results thus help to understand the relationship between ecological and sexual selection pressure operating on signalers and how in turn this may influence multimodal signal evolution.

evolutionary biology↗

bioRxiv2021

Construction of a potent pan-vaccine based on the evolutionary tendency of SARS-CoV-2 spike protein.

SARS-CoV-2 continued to spread globally along with different variants. Here, we systemically analyzed viral infectivity and immune-resistance of SARS-CoV-2 variants to explore the underlying rationale of viral mutagenesis. We found that the Beta variant harbors both high infectivity and strong immune resistance, while the Delta variant is the most infectious with only a mild immune-escape ability. Remarkably, the Omicron variant is even more immune-resistant than the Beta variant, but its infectivity increases only in Vero E6 cells implying a probable preference for the endocytic pathway. A comprehensive analysis revealed that SARS-CoV-2 spike protein evolved into distinct evolutionary paths of either high infectivity plus low immune resistance or low infectivity plus high immune resistance, resulting in a narrow spectrum of the current single-strain vaccine. In light of these findings and the phylogenetic analysis of 2674 SARS-CoV-2 S-protein sequences, we generated a consensus antigen (S6) taking the most frequent mutations as a pan-vaccine against heterogeneous variants. As compared to the ancestry SWT vaccine with significantly declined neutralizations to emerging variants, the S6 vaccine elicits broadly neutralizing antibodies and full protections to a wide range of variants. Our work highlights the importance and feasibility of a universal vaccine strategy to fight against antigen drift of SARS-CoV-2.

microbiology↗

bioRxiv2021

The first sheep graph pan-genome reveals the spectrum of structural variations and their effects on different tail phenotypes

Structural variations (SVs) are a major contributor to genetic diversity and phenotypic variations, but their prevalence and functions in domestic animals are largely unexplored. Here, we assembled 26 haplotype-resolved genome assemblies from 13 genetically diverse sheep using PacBio HiFi sequencing. We constructed a graph-based ovine pan-genome and discovered 142,422 biallelic insertions and deletions, 7,028 divergent alleles and 13,419 multiallelic variations. We then used a graph-based approach to genotype the biallelic SVs in 684 individuals from 45 domestic breeds and two wild species. Integration with RNA-seq data allows to identify candidate expression-associated SVs. We demonstrate a direct link of SVs and phenotypes by localizing the putative causative insertion in HOXB13 gene responsible for the long-tail trait and identifying multiple large SVs associated with the fat-tail. Beyond generating a benchmark resource for ovine structural variants, our study highlights that animal genetic research will greatly benefit from using a pan-genome graph rather than a single reference genome.

genomics↗