Biology subjects

Yang, Z.

Publications and source records attributed to Yang, Z..

At least 451 records · Page 25Linked to original sources

bioRxiv2021

Emergence of an adaptive epigenetic cell state in human bladder urothelial carcinoma evolution

Intratumor heterogeneity (ITH) of bladder cancer (BLCA) facilitates therapy resistance and immune evasion to affect clinical prognosis directly. However, the molecular and cellular mechanism generating ITH in BLCA remains elusive. Here we show that a TM4SF1-positive cancer subpopulation (TPCS) drives ITH diversification in BLCA. By extensive profiling of the epigenome and transcriptome of BLCA from 79 donors across all stages, we elucidated the evolution trajectories of luminal and basal BLCA. TPCS emerges from the basal trajectory and shows extensive transcriptional plasticity with a distinct epigenomic landscape. Clinically, TPCS were enriched in advanced stage patients and associated with poor prognosis. Our results showed how cancer adapts to its environment by adopting a stem cell-like epigenomic landscape.

cancer biology↗

bioRxiv2021

Mandrake: visualising microbial population structure by embedding millions of genomes into a low-dimensional representation

In less than a decade, population genomics of microbes has progressed from the effort of sequencing dozens of strains to thousands, or even tens of thousands of strains in a single study. There are now hundreds of thousands of genomes available even for a single bacterial species and the number of genomes is expected to continue to increase at an accelerated pace given the advances in sequencing technology and widespread genomic surveillance initiatives. This explosion of data calls for innovative methods to enable rapid exploration of the structure of a population based on different data modalities, such as multiple sequence alignments, assemblies and estimates of gene content across different genomes. Here we present Mandrake, an efficient implementation of a dimensional reduction method tailored for the needs of large-scale population genomics. Mandrake is capable of visualising population structure from millions of whole genomes and we illustrate its usefulness with several data sets representing major pathogens. Our method is freely available both as an analysis pipeline (https://github.com/johnlees/mandrake) and as a browser-based interactive application (https://gtonkinhill.github.io/mandrake-web/).

genomics↗

bioRxiv2021

Double-check the zebrafish 18s rRNA qPCR primers: they may be wrong

A widely used qPCR primer for zebrafish gene rna18s (18s rRNA, or 18s), with the sequence of 5-TCGCtaGTtGGCATCGTTTAtG-3, is found to be incorrect. Initially designed for rainbow trout (Oncorhynchus mykiss) rna18s, the primer has four different nucleotides from the zebrafish sequence 5-TCGCGGGTCGGCATCGTTTACG-3 (indicated in bold/underlined, lowercase letters for rainbow trout and uppercase letters for zebrafish). Since its first use in zebrafish in 2006, this mismatched primer has been clearly stated to be used in at least 50 publications and may have affected hundreds or more in publications citing them. For a sensitive, quantitative method as qPCR, this error must be corrected as soon as possible in the zebrafish community by using rna18s primer sets with accurate sequences, such as those summarized and newly designed in this article.

molecular biology↗

bioRxiv2021

A poxvirus decapping enzyme localizes to mitochondria to regulate RNA metabolism and translation, and promote viral replication

Decapping enzymes remove the 5-cap of eukaryotic mRNA, leading to accelerated RNA decay. They are critical in regulating RNA homeostasis and play essential roles in many cellular and life processes. They are encoded in many organisms and viruses, including vaccinia virus, which was used as the vaccine to eradicate smallpox. Vaccinia virus encodes two decapping enzymes, D9 and D10, that are necessary for efficient viral replication and pathogenesis. However, the underlying molecular mechanism regulating vaccinia decapping enzymes function is still largely elusive. Here we demonstrated that vaccinia D10 localized almost exclusively to mitochondria that are highly mobile cellular organelles, providing an innovative mechanism to concentrate D10 locally and mobilize it to efficiently decap mRNAs. As mitochondria were barely present in "viral factories," where viral transcripts are produced, suggesting that mitochondrial localization provides a spatial mechanism to preferentially decap cellular mRNAs over viral mRNAs. We identified three amino acids responsible for D10s mitochondrial localization. Loss of mitochondrial localization significantly impaired viral replication, reduced D10s ability to resolve RNA 5-cap aggregation during infection, diminished D10s gene expression shutoff and mRNA translation promotion abilities. ImportanceDecapping enzymes comprise many members from various organisms ranging from plants, animals, and viruses. The mechanisms regulating their functions vary and are still largely unknown. Our study provides the first mitochondria-localized decapping enzyme, D10, encoded by vaccinia virus that was used as the vaccine to eradicate smallpox. Loss of mitochondrial localization significantly impaired viral replication and D10s gene expression shutoff and mRNA translation promotion ability. Mitochondrial localization is a spatial mechanism to concentrate D10 locally and mobilize it to efficiently and preferentially target cellular mRNAs for decapping and promote viral mRNA translation. Our results have broad impacts on understanding the functions and mechanisms of decapping enzymes.

microbiology↗

bioRxiv2021

Severe fever with thrombocytopenia syndrome virus and parthenogenetic Asian longhorned tick Haemaphysalis longicornis (Acari: Ixodidae)

Severe fever with thrombocytopenia syndrome virus (SFTSV) is spreading rapidly in Asia. It is transmitted by Haemaphysalis longicornis (Asian longhorned tick, ALT), which has both parthenogenetically and sexually reproducing populations. Parthenogenetic populations were found in at least 15 provinces in China and strongly correlated with the distribution of SFTS. The distribution of SFTS cases was however poorly correlated with the distribution of populations of bisexual ALTs. Phylogeographic analysis suggested that the parthenogenetic population spread much faster than bisexual population because colonization is independent of sexual reproduction. A higher proportion of parthenogenetic ALTs were collected from migratory birds captured at an SFTS endemic area, implicating the contribution to the long-range movement of ALTs in China. The SFTSV susceptibility of parthenogenetic females was like that of bisexual females under laboratory conditions. These results suggest that parthenogenetic ALT, probably transported by migratory birds, play a major role in the rapid spread of SFTSV. Article Summary LineThe parthenogenetic population of Asian longhorned tick is broadly distributed in China and plays a major role in the long-distance spread of SFTSV and perhaps future invasion of countries outside of Asia.

evolutionary biology↗

bioRxiv2021

SARS-CoV-2 variants exhibit increased kinetic stability of open spike conformations as an evolutionary strategy

SARS-CoV-2 variants of concern harbor mutations in the Spike (S) glycoprotein that confer more efficient transmission and dampen the efficacy of COVID-19 vaccines and antibody therapies. S mediates virus entry and is the primary target for antibody responses. Structural studies of soluble S variants have revealed an increased propensity towards conformations accessible to receptor human Angiotensin-Converting Enzyme 2 (hACE2). However, real-time observations of conformational dynamics that govern the structural equilibriums of the S variants have been lacking. Here, we report single-molecule Forster Resonance Energy Transfer (smFRET) studies of S variants containing critical mutations, including D614G and E484K, in the context of virus particles. Investigated variants predominantly occupied more open hACE2-accessible conformations, agreeing with previous structures of soluble trimers. Additionally, these S variants exhibited decelerated transitions in hACE2-accessible/bound states. Our finding of increased S kinetic stability in the open conformation provides a new perspective on SARS-CoV-2 adaptation to the human population.

microbiology↗

bioRxiv2021

Maternal mRNA deadenylation is defective in in vitro matured mouse and human oocytes

Oocyte in vitro maturation is a technique of assisted reproductive technology that was first introduced in patients with polycystic ovarian syndrome and is now used in most fertility clinics. Thousands of genes show abnormally high expression in in vitro maturated metaphase II (in vitro MII) oocytes compared with in vivo maturated metaphase II (in vivo MII) oocytes in bovines, mice, and humans1-3. However, the underlying mechanisms of this abnormal expression are still poorly understood. In this study, we use PAIso-seq1 to reveal a transcriptome-wide expression profile of full-length transcripts containing entire poly(A) tails in in vivo and in vitro matured mouse and human oocytes. Our results indicate that more genes are up-regulated than down-regulated in in vitro MII oocytes in both mice and humans. Furthermore, we demonstrate that the observed increase in maternal mRNA abundance is caused by impaired deadenylation in in vitro MII oocytes in both mice and humans. We also found that the cytoplasmic polyadenylation of dormant Btg4 and Cnot7 mRNAs, which encode key components of deadenylation machinery, is impaired in in vitro MII oocytes in mice and humans respectively, likely contributing to reduced translation and impaired global maternal mRNA deadenylation. Our findings highlight that impaired maternal mRNA deadenylation is a definite molecular defect in in vitro MII oocytes in both mice and humans. The findings here offer a new criterion for evaluating the quality of in vitro MII oocytes and a potential direction for improving in vitro maturation by fixing the dysregulated maternal mRNA deadenylation.

developmental biology↗

bioRxiv2021

Estimation of Cross-Species Introgression Rates using Genomic Data Despite Model Unidentifiability

Full likelihood implementations of the multispecies coalescent with introgression (MSci) model takes the genealogical fluctuation across the genome as a major source of information to infer the history of species divergence and gene flow using multilocus sequence data. However, MSci models are known to have unidentifiability issues, whereby different models or parameters make the same predictions about the data and cannot be distinguished by the data. Previous studies have focused on heuristic methods based on gene trees, and does not make an efficient use of the information in the data. Here we study the unidentifiability of MSci models under the full likelihood methods. We characterize the unidentifiability of the bidirectional introgression (BDI) model, which assumes that gene flow occurs in both directions. We derive simple rules for arbitrary BDI models, which create unidentifiability of the label-switching type. In general, an MSci model with k BDI events has 2k unidentifiable modes or towers in the posterior, with each BDI event between sister species creating within-model parameter unidentifiability and each BDI event between non-sister species creating between-model unidentifiability. We develop novel algorithms for processing Markov chain Monte Carlo (MCMC) samples to remove label-switching problems and implement them in the BPP program. We analyze real and synthetic data to illustrate the utility of the BDI models and the new algorithms. We discuss the unidentifiability of heuristic methods and provide guidelines for the use of MSci models to infer gene flow using genomic data.

evolutionary biology↗

bioRxiv2021

RADseq data reveal a lack of admixture in a mouse lemur contact zone contrary to previous microsatellite results

Despite being one of the most fundamental biological processes, the process of speciation remains poorly understood in many groups of organisms. Mouse lemurs are a species-rich genus of small primates endemic to Madagascar, whose diversity has only recently been uncovered using genetic data and is primarily found among morphologically cryptic, allopatric populations. To assess to what extent described species represent reproductively isolated entities, studies are needed in areas where mouse lemur taxa come into contact. Hybridization has previously been reported in a contact zone between two closely related mouse lemur species (Microcebus murinus and M. griseorufus) based on microsatellite data. Here, we revisit this system using RADseq data for populations in, near, and far from the contact zone, including many of the individuals that had previously been identified as hybrids. Surprisingly, we find no evidence for admixed nuclear ancestry in any of the individuals. Re-analyses of microsatellite data and simulations suggest that previously inferred hybrids were false positives and that the program NewHybrids can be particularly sensitive to erroneously inferring hybrid ancestry. Using coalescent-bases analyses, we also show an overall lack of recent gene flow between the two species, and low levels of ancestral gene flow. Combined with evidence for local syntopic occurrence, these data indicate that M. murinus and M. griseorufus are reproductively isolated. Finally, we estimate that they diverged less than a million years ago, suggesting that completion of speciation is relatively rapid in mouse lemurs. Future work should focus on the underpinnings of reproductive isolation in this cryptic primate radiation, which are mostly unknown. Our study also provides a cautionary tale for the inference of hybridization with microsatellite data.

evolutionary biology↗

bioRxiv2021

Genetic loci of the R. anatipestifer serotype discovered by Pan-GWAS and its application for the development of a multiplex PCR serotyping method

The disease caused by Riemerella anatipestifer (R. anatipestifer) causes large economic losses to the global duck industry every year. Serotype-related genomic variation (such as in O-antigen and capsular polysaccharide gene clusters) has been widely used for the serotyping in many gram-negative bacteria. To date, there have been few studies focused on genetic basis of serotypes in R. anatipestifer. Here, we used pan-genome-wide association studies (Pan-GWAS) to identify the serotype-specific genetic loci of 38 R. anatipestifers strain. Analyses of the loci of 11 serotypes showed that the loci could be well mapped with the serotypes of the corresponding strains. We constructed the knockout strain for the wzy gene at the locus, and the results showed that the mutant lost the agglutination characteristics to positive antisera. Based on the of Pan-GWAS results, we developed a multiple PCR method to identify serotypes 1, 2, and 11 of R. anatipestifer. Our study provides a precedent for systematically analysing the genetic basis of the R anatipestifer serotypes and establishing a complete serotyping system in the future. HighlightsO_LIR. anatipestifer serotype-specific locus was identified by Pan-GWAS for the first time. C_LIO_LIMolecular serotyping multiplex PCR was developed based on O-antigen biosynthesis gene clusters C_LI

genomics↗

bioRxiv2021

BAI-Net: Individualized Human Cerebral Cartography using Graph Convolutional Network

Brain atlas is an important tool in the diagnosis and treatment of neurological disorders. However, due to large variations in the organizational principles of individual brains, many challenges remain in clinical applications. Brain atlas individualization network (BAI-Net) is an algorithm that subdivides individual cerebral cortex into segregated areas using brain morphology and connectomes. BAI-Net integrates topological priors derived from a group atlas, adjusts the areal probability using the connectivity context derived from diffusion tractography, and provides reliable and explainable individualized brain parcels across multiple sessions and scanners. We demonstrate that BAI-Net outperforms the conventional iterative clustering approach by capturing significantly heritable topographic variations in individualized cartographies. The topographic variability of BAI-Net cartographies shows strong associations with individual variability in brain morphology, connectivity fingerprints and cognitive behaviors. This study provides a new framework for individualized brain cartography and paves the way of atlas-based precision medicine in clinical practice.

neuroscience↗

bioRxiv2021

WDR82-binding long non-coding RNA lncEry controls mouse erythroid differentiation and maturation

Hematopoietic differentiation is controlled by both genetic and epigenetic regulators. Long non-coding RNAs (lncRNAs) have been demonstrated to be important for normal hematopoiesis, but their function in erythropoiesis needs to be further explored. We profiled the transcriptomes of 16 murine hematopoietic cell populations by deep RNA-sequencing and identified a novel lncRNA, Gm15915, that was highly expressed in erythroid-related progenitors and erythrocytes. For this reason, we named it lncEry. We also identified a novel lncEry isoform, which was also the principal transcript that has not been reported before. LncEry depletion impaired erythropoiesis, indicating the important role of the lncRNA in regulating erythroid differentiation and maturation. Mechanistically, we found that lncEry interacted with WD repeat-containing protein 82 (WDR82) to promote the transcription of Klf1 and globin genes and thus control the early and late stages of erythropoiesis, respectively. These findings identified lncEry as an important player in the transcriptional regulation of erythropoiesis.

cell biology↗

bioRxiv2021

ERp44 is Required for Endocardial Cushion Development by Regulating VEGFA Secretion in Myocardium

Rationale: Endocardial cushions are precursors of the valvoseptal complex that separates the four heart chambers and control blood flow through the heart. Abnormalities in endocardial cushion development lead to atrioventricular septal defects (AVSDs), which affect 1 in 2,100 live births. Several genes have been implicated in the development of endocardial cushions. Specifically, endoplasmic reticulum-resident protein 44 (ERp44) has been found to play a role in the early secretory pathway, but its function in heart development has not been well studied. Objective: The goal of this study was to investigate the role of ERp44 in heart development in mice. Approach and Results: Using conventional and tissue-specific knockout mouse models, we demonstrated that ERp44 plays a specific role in heart development. ERp44 knockout (KO) mice were smaller in size, and most mice died during early postnatal life. KO hearts exhibited the typical phenotypes of congenital heart diseases, such as abnormal heart shapes as well as severe septal and valvular defects. Similar phenotypes were found in cTnt-cre+/-; Erp44fl/fl mice, which indicated that myocardial ERp44 principally controls endocardial cushion formation. Further studies demonstrated that the deletion of ERp44 significantly decreased the proliferation of cushion cells and impaired the endocardial-mesenchymal transition (EndMT), which was followed by endocardial cushion dysplasia. Finally, we found that ERp44 directly bound to VEGFA and controlled its release. Conclusions: ERp44 contributes to the development of the endocardial cushion by affecting the EndMT of cushion cells by regulating VEGFA release in myocardial cells.

developmental biology↗

bioRxiv2021

Uncovering the Genetic Profiles Underlying the Intrinsic Organization of the Human Cerebellum

The functional diversity of the human cerebellum is largely believed to be derived more from its extensive connections rather than being limited to its mostly invariant architecture. However, whether and how the determination of cerebellar connections in its intrinsic organization interact with microscale gene expression is still unknown. Here we decode the genetic profiles of the cerebellar functional organization by investigating the genetic substrates simultaneously linking cerebellar functional heterogeneity and its drivers, i.e., the connections. We not only identified 443 network-specific genes but also discovered that their co-expression pattern correlated strongly with intra-cerebellar functional connectivity (FC). Ninety of these genes were also linked to the FC of cortico-cerebellar cognitive-limbic networks. To further discover the biological functions of these genes, we performed a "virtual gene knock-out" by observing the change in the coupling between gene co-expression and FC and divided the genes into two subsets, i.e., a positive gene contribution indicator (GCI+) involved in cerebellar neurodevelopment and a negative gene set (GCI-) related to neurotransmission. A more interesting finding is that GCI- is significantly linked with the cerebellar connectivity-behavior association and many recognized brain diseases that are closely linked with the cerebellar functional abnormalities. Our results could collectively help to rethink the genetic substrates underlying the cerebellar functional organization and offer possible micro-macro interacted mechanistic interpretations of the cerebellum-involved high order functions and dysfunctions in neuropsychiatric disorders.

neuroscience↗

bioRxiv2021

CamelliA-based simultaneous imaging of Ca2+ dynamics in subcellular compartments

As a universal second messenger, calcium (Ca2+) transmits specific cellular signals via a spatiotemporal signature generated from its extracellular source and internal stores. Our knowledge of the mechanisms underlying generation of a Ca2+ signature is hampered by limited tools enabling simultaneous monitoring of the dynamics of Ca2+ levels in multiple subcellular compartments. To overcome the limitation and to further improve spatiotemporal resolutions, here we have assembled a molecular toolset (the CamelliA lines) in Arabidopsis that enables simultaneous and high-resolution monitoring of Ca2+ dynamics in multiple subcellular compartments through imaging analyses of different single-colored GECIs (Genetically Encoded Calcium Indicators). Indeed, the uncovering of the previously unrecognized Ca2+ signatures in three types of Arabidopsis cells in response to internal and external cues is a testimony to the wide applicability of the newly generated toolset for elucidating the subcellular sources contributing to the Ca2+signatures in plants. One sentence summaryA toolset for simultaneous imaging of Ca2+ dynamics in subcellular compartments has uncovered unrecognized Ca2+ signatures in Arabidopsis cells in response to developmental and external cues.

plant biology↗

bioRxiv2021

Genome of the giant panda roundworm illuminates its host shift and parasitic adaptation

Baylisascaris schroederi, a bamboo-feeding giant panda (Ailuropoda melanoleuca)-specific roundworm (ascaridoid) parasite, is the causative agent of baylisascariasis, which represents a leading reason for the mortality of wild giant panda populations and therefore poses a significant threat to giant panda conservation. Here we present a 293-Mb chromosome-level genome assembly of B. schroederi to inform its biology, including host adaptations. Comparative genomics revealed an evolutionary trajectory accompanied by host-shift events in ascaridoid parasite lineages after host separations, suggesting their potential transmissions and fast adaptations to hosts. Genomic and anatomical lines of evidence, including expansion and positive selection of genes related to cuticle and basal metabolisms, indicates that B. schroederi undergoes specific adaptations to survive in the sharp-edged bamboo enriched gut of giant panda by structurally increasing its cuticle thickness and efficiently utilizing host nutrients during gut parasitism. Also, we characterized the secretome and predicted potential drug and vaccine targets for new interventions. Overall, this genome resource provides new insights into the host adaptation of B. schroederi to giant panda as well as the host-shift events in ascaridoid parasite lineages. These findings also add to our knowledge on the unique biology of the giant panda roundworm and aid the development of much-needed novel strategies for the control of baylisascariasis and thus the protection of giant panda populations.

genomics↗

bioRxiv2021

Comprehensive Analysis of Spatial Architecture in Primary Liver Cancer

Heterogeneity is the major challenge for cancer prevention and therapy. Here, we firstly constructed high-resolution spatial transcriptomes of primary liver cancers (PLCs) containing 84,823 spots within 21 tissues from 7 patients. The sequential comparison of spatial tumor microenvironment (TME) characteristics from non-tumor to leading-edge to tumor regions revealed that the tumor capsule potentially affects intratumor spatial cluster continuity, transcriptome diversity and immune cell infiltration. Locally, we found that the bidirectional ligand-receptor interactions at the 100 m wide cluster-cluster boundary contribute to maintaining intratumor architecture. Our study provides novel insights for diverse tumor ecosystem of PLCs and has potential benefits for cancer intervention.

cancer biology↗

bioRxiv2021

HIV-1 Nef and CycK:CDK13 antagonize SERINC5 for optimal viral infectivity

HIV-1 Nef antagonizes SERINC5 by redirecting this potent restriction factor to the endosomes and lysosomes for degradation. However, the precise mechanism remains unclear. Using affinity purification/mass spectrometry, we identified cyclin K and cyclin-dependent kinase 13 (CycK:CDK13) as a new Nef-associated kinase complex. CycK:CDK13 phosphorylates the serine at position 360 (S360) in SERINC5, which is required for Nef downregulation of SERINC5 from the cell surface and its counter activity of the SERINC5 antiviral activity. To understand the role of S360 phosphorylation, we created chimeric proteins between CD8 and SERINC5. Nef not only downregulates, but importantly, also binds to this chimera in a S360-dependent manner. Thus, S360 phosphorylation increases interactions between Nef and SERINC5 and initiates the destruction of SERINC5 by the endocytic machinery.

microbiology↗