Biology subjects

Wei, Y.

Publications and source records attributed to Wei, Y..

At least 163 records · Page 9Linked to original sources

bioRxiv2023

T2T-YAO: a Telomere-to-telomere Assembled Diploid Reference Genome for Han Chinese

Since its initial release in 2001, the human reference genome has been continuously improved in both continuity and accuracy, and the recently-released telomere-to-telomere version--T2T-CHM13--reaches its top quality after 20 years of effort. However, T2T-CHM13 does not represent an authentic diploid human genome, but rather one derived from a simplified, nearly homozygous genome of a hydatidiform mole cell line. To address this limitation and provide an alternative pertinent to the Chinese population, the largest ethnic group in the world, we have assembled a complete diploid human genome of a male Han Chinese, T2T-YAO, which includes telomere-to-telomere assemblies for all the 22+X+M and 22+Y chromosomes in his two haploids inherited separately from his parents. Both haplotypes contain no artificial sequences or model nucleotides and possess a high quality comparable to CHM13, with fewer than one error per [~]14 Mb. Derived from the individual who lives in the aboriginal region of Han Chinese, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors of the Han population. Each haplotype of T2T-YAO possesses [~]340 Mb exclusive sequences and [~]3100 unique genes as compared to CHM13, and their genome sequences show greater genetic distance to CHM13 than to each other in terms of nucleotide polymorphism and structural variations. The construction of T2T-YAO would serve as a high-quality diploid reference that enables precise delineation of genomic variations in a haplotype-sensitive manner, which could advance our understandings in human evolution, hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.

genetics↗

bioRxiv2023

Maresin-2 Fine-tunes ULK1 O-GlcNAcylation to Improve Post Myocardial Infarction Remodeling

Maresin-2, a specialized pro-solving mediator of inflammation has been consolidated to be a novel cytokine fine-tuning inflammatory cascade. However, the underlying molecular basis is still largely unknown. Focused on cardiac dysfunction and remodeling, we employed in vivo- and in vitro- based genome editing methodology tools including adenosine associated virus, adenosine virus, lenti-virus, plasmid transfection, and CRISPR-Cas9 methodology for investigation. As suggested, exogenous maresin-2 supplement facilitated autophagosome formation by microtubule-associated proteins 1A/1B light chain 3B (LC3) conjugation system under the modulation of O-GlcNAcylation dependent ULK1 activation, whereas reversed by ULK1 S409A and S422A mutagenesis, showcasing the potential O-GlcNAc (O-linked {beta}- N-acetylglucosamine) modifiable sites on ULK1. Moreover, we found that hereafter maresin-2 treatment glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1) which is accessary to sense hexosamine biosynthesis influx is more likely the prime checkpoint for conjugating O-terminal {beta}-N-acetylglucosamine motif onto ULK1, rather than O-linked N-acetylglucosaminyltransferase (OGT). Mechanistically, maresin-2 largely prohibits transforming growth factor-{beta} (TGF-{beta})-activated kinase 1 (TAK1), therefore increasing the availability of TAB1 for GFAT1, which encourages O-GlcNAcylation of ULK1.

molecular biology↗

bioRxiv2023

Nucleolar detention of NONO shields DNA double-strand breaks from aberrant transcripts

RNA-binding proteins (RBPs) stimulate the DNA damage response (DDR). The RBP NONO marks nuclear paraspeckles in unperturbed cells and undergoes poorly understood re-localisation to the nucleolus upon induction of DNA double-strand breaks (DSBs). Here we show that treatment with the topoisomerase-II inhibitor etoposide stimulates the production of RNA polymerase II-dependent, DNA damage-induced nucleolar antisense RNAs (diNARs) in human cells. diNARs originate from the nucleolar intergenic spacer and tether NONO to the nucleolus via its RRM1 domain. NONO occupancy at protein-coding gene promoters is reduced by etoposide, which attenuates pre-mRNA synthesis, enhances NONO binding to pre-mRNA transcripts and is accompanied by nucleolar detention of such transcripts. The depletion or mutation of NONO interferes with detention and prolongs DSB signaling. Together, we describe a nucleolar DDR pathway that shields NONO and aberrant transcripts from DSBs to promote DNA repair.

molecular biology↗

bioRxiv2023

Distinct Neurodevelopmental Patterns and Intermediate Integration-Based Predictive Modeling in Autism Spectral Disorder

Autism Spectrum Disorder (ASD) is known to exhibit a more rapid expansion in brain structure during the early years of life compared to typically developing children (TD). This is of utmost importance in understanding atypical brain development and forecasting the onset of ASD. However, the precise age-related cortical changes (trajectories) that could pinpoint atypical brain development in ASD remain largely unknown. In this study, we characterize the distinct developmental patterns of cortical morphology in individuals with ASD, investigate the important neural biomarkers for ASD diagnostics, and propose a deep-learning workflow that combined graph convolutional networks with low-rank multi-model tensor fusion (LMFGCN) for ASD prediction. Our findings reveal that the constituents of gray matter volume (GV), cortical thickness (CT), and surface area (SA) exhibit separable developmental trajectories in ASD. Furthermore, we identify regional differences in CT and SA that underscore the separable brain developmental trajectories, both of which contribute to changes in GV. Our study also demonstrates that LMFGCN, an end-to-end deep-learning model with intermediate integrative approach, outperforms early and late integration methods and other state-of-the-art models in ASD classification. Overall, our results highlight the importance of distinguishing between cortical SA and CT for understanding ASD pathobiology, particularly during the early brain overgrowth period, and demonstrate the potential utility of LMFGCN in ASD classification.

neuroscience↗

bioRxiv2023

Lysine vitcylation is a novel vitamin C-derived protein modification that enhances STAT1-mediated immune response

Vitamin C (vitC) is a vital nutrient for health and also used as a therapeutic agent in diseases such as cancer. However, the mechanisms underlying vitCs effects remain elusive. Here we report that vitC directly modifies lysine without enzymes to form vitcyl-lysine, termed "vitcylation", in a dose-, pH-, and sequence-dependent manner across diverse proteins in cells. We further discover that vitC vitcylates K298 site of STAT1, which impairs its interaction with the phosphatase PTPN2, preventing STAT1 Y701 dephosphorylation and leading to increased STAT1-mediated IFN pathway activation in tumor cells. As a result, these cells have increased MHC/HLA class-I expression and activate immune cells in co-cultures. Tumors collected from vitC-treated tumor-bearing mice have enhanced vitcylation, STAT1 phosphorylation and antigen presentation. The identification of vitcylation as a novel PTM and the characterization of its effect in tumor cells opens a new avenue for understanding vitC in cellular processes, disease mechanisms, and therapeutics.

biochemistry↗

bioRxiv2023

Quantile Regression for biomarkers in the UK Biobank

Genome-wide association studies (GWAS) for biomarkers important for clinical phenotypes can lead to clinically relevant discoveries. GWAS for quantitative traits are based on simplified regression models modeling the conditional mean of a phenotype as a linear function of genotype. An alternative and easy to apply approach is quantile regression that naturally extends linear regression to the analysis of the entire conditional distribution of a phenotype of interest by modeling conditional quantiles within a regression framework. Quantile regression can be applied efficiently at biobank scale using standard statistical packages in much the same way as linear regression, while having some unique advantages such as identifying variants with heterogeneous effects across different quantiles, including non-additive effects and variants involved in gene-environment interactions; accommodating a wide range of phenotype distributions with invariance to trait transformation; and overall providing more detailed information about the underlying genotype-phenotype associations. Here, we demonstrate the value of quantile regression in the context of GWAS by applying it to 39 quantitative traits in the UK Biobank (n > 300, 000 individuals). Across these 39 traits we identify 7,297 significant loci, including 259 loci only detected by quantile regression. We show that quantile regression can help uncover replicable but unmodelled gene-environment interactions, and can provide additional key insights into poorly understood genotype-phenotype correlations for clinically relevant biomarkers at minimal additional cost.

genomics↗

bioRxiv2023

Associations between in vitro, in vivo and in silico cell classes in mouse primary visual cortex

The brain consists of many cell classes yet in vivo electrophysiology recordings are typically unable to identify and monitor their activity in the behaving animal. Here, we employed a systematic approach to link cellular, multi-modal in vitro properties from experiments with in vivo recorded units via computational modeling and optotagging experiments. We found two one-channel and six multi-channel clusters in mouse visual cortex with distinct in vivo properties in terms of activity, cortical depth, and behavior. We used biophysical models to map the two one- and the six multi-channel clusters to specific in vitro classes with unique morphology, excitability and conductance properties that explain their distinct extracellular signatures and functional characteristics. These concepts were tested in ground-truth optotagging experiments with two inhibitory classes unveiling distinct in vivo properties. This multi-modal approach presents a powerful way to separate in vivo clusters and infer their cellular properties from first principles.

neuroscience↗

bioRxiv2023

Interspecies blastocyst complementation generates functional rat cell-derived forebrain tissues in mice

Interspecies organogenesis via blastocyst complementation provides a unique platform to study development in an evolutionarily context and holds potential to overcome world-wide organ shortages1. By using this technique, rat pancreas, thymus, heart, and eye tissues have been generated in mice2-4. To date, however, xeno-generation of brain tissues has not been achieved through blastocyst complementation. Here, we developed an optimized one-step blastocyst complementation strategy based on C-CRISPR5, which facilitated rapid screening of candidate genes to support blastocyst complementation. Among the seven WNT pathway-related genes selected for targeting, only Dkk1 or Hesx1 deficiency supported forebrain complementation by blastocyst injection of mouse embryonic stem cells (mESCs). Further, injecting rat ESCs (rESCs) into mouse blastocysts deficient for Hesx1 but not Dkk1 supported the development of adult chimeric forebrains comprised a large proportion of rat cells that were structurally and functionally similar to the mouse forebrains. Our analysis revealed that the rESC-derived forebrains developed along the spatial-temporal trajectory with the mouse forebrains rather than rat forebrains, but gene expression profiles of rESC-derived nerve cells surprisingly maintained the characteristics of the rat cells. We noted that the chimeric rate gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late prenatal development. Interspecies forebrain complementation opens the door for studying evolutionarily conserved and divergent mechanisms underlying brain development and cognitive function. The C-CRIPSR based IBC strategy developed here holds great potential to broaden the study and application of interspecies organogenesis.

developmental biology↗

bioRxiv2023

Dissecting embryonic and extra-embryonic lineage crosstalk with stem cell co-culture

Faithful embryogenesis requires precise coordination between embryonic and extraembryonic tissues. Although stem cells from embryonic and extraembryonic origins have been generated for several mammalian species(Bogliotti et al., 2018; Choi et al., 2019; Cui et al., 2019; Evans and Kaufman, 1981; Kunath et al., 2005; Li et al., 2008; Martin, 1981; Okae et al., 2018; Tanaka et al., 1998; Thomson et al., 1998; Vandevoort et al., 2007; Vilarino et al., 2020; Yu et al., 2021b; Zhong et al., 2018), they are grown in different culture conditions with diverse media composition, which makes it difficult to study cross-lineage communication. Here, by using the same culture condition that activates FGF, TGF-{beta} and WNT signaling pathways, we derived stable embryonic stem cells (ESCs), extraembryonic endoderm stem cells (XENs) and trophoblast stem cells (TSCs) from all three founding tissues of mouse and cynomolgus monkey blastocysts. This allowed us to establish embryonic and extraembryonic stem cell co-cultures to dissect lineage crosstalk during early mammalian development. Co-cultures of ESCs and XENs uncovered a conserved and previously unrecognized growth inhibition of pluripotent cells by extraembryonic endoderm cells, which is in part mediated through extracellular matrix signaling. Our study unveils a more universal state of stem cell self-renewal stabilized by activation, as opposed to inhibition, of developmental signaling pathways. The embryonic and extraembryonic stem cell co-culture strategy developed here will open new avenues for creating more faithful embryo models and developing more developmentally relevant differentiation protocols.

developmental biology↗

bioRxiv2023

A promising QTL QSns.sau-MC-3D.1 likely superior to WAPO1 for wheat spikelet number per spike shows no adverse effects on yield-related traits

Spikelet number per spike (SNS) is one of the crucial factors determining wheat yield. Thus, improving our understanding of the genes that regulate SNS could help develop higher-yielding wheat varieties. A genetic linkage map constructed using the GenoBaits Wheat 16K Panel and the 660K SNP array contained 5991 polymorphic SNP markers spanning 2813.26 cM. A total of twelve QTL for SNS were detected in the recombinant inbred line (RIL) population msf x Chuannong 16 (MC), and two of them, i.e., QSns.sau-MC-3D.1 and QSns.sau-MC-7A, were stably expressed. QSns.sau-MC-3D.1 had high LOD values ranging from 4.99 to 11.06 and explained 9.71-16.75% of the phenotypic variation. Comparison of QSns.sau-MC-3D.1 with previously reported SNS QTL suggested that it is likely a novel one. A kompetitive allele-specific PCR (KASP) marker, KASP-10, tightly linked to QSns.sau-MC-3D.1 was developed to successfully validate its effect in three segregated populations and a natural population. Genetic analysis indicated that WHEAT ORTHOLOG OFAPO1 (WAPO1) was a candidate gene for QSns.sau-MC-7A. The combined additive effect of QSns.sau-MC-3D.1 and WAP01 had a great additive effect increasing SNS by 7.10%. In addition, our results suggested that SNS is not affected by 1BL/1RS translocations in the MC RIL population. Correlation analysis between two major QTL and other agronomic traits showed that QSns.sau-MC-3D.1 was likely independent of these agronomic traits. However, the H2 haplotype of WAPO1 may affect effective tiller number and plant height. This indicated that the breeding potential of QSns.sau-MC-3D.1 is better than that of WAPO1. The geographical distribution of QSns.nsau-MC-3D.1 showed that QSns.sau-MC-3D.1 positive allele frequency was dominant in most wheat-producing regions of China and it has been positively selected among modern cultivars released in China since the 1940s. Two genes, TraesCS3D03G0222600 and TraesCS3D03G0216800, associated with SNS development were predicted in the physical interval of QSns.sau-MC-3D.1. qRT-PCR results of the two genes showed that only the expression level of TraesCS3D03G0216800 was significantly different between msf and CN16. These results enrich our understanding of the genetic basis of wheat SNS and will be useful for fine mapping and cloning of genes underlying QSns.sau-MC-3D.1, and provide a basis for marker-assisted selection breeding. Author summaryIn this study, we identified two major QTL (QSns.sau-MC-3D.1 and QSns.sau-MC-7A) in a RIL population. WAPO1 was demonstrated to be the candidate gene for QSns.sau-MC-7A. QSns.sau-MC-3D.1 was a novel and stably expressed QTL, and further confirmed in different genetic backgrounds. Our results further demonstrate that QSns.sau-MC-3D.1 has better breeding potential because of its no adverse effect on other agronomic traits than WAPO1, and it has been positively selected during Chinese breeding programs since the 1940s. Taken together, the identification of QSns.sau-MC-3D.1 offers a promising resource to further increase wheat yields.

genetics↗

bioRxiv2023

An Unexpected Role of Neutrophils in Clearing Apoptotic Hepatocytes In Vivo

Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal cells). Despite being a type of professional phagocyte, neutrophils are thought to be excluded from apoptotic sites to avoid tissue inflammation. Here we report a fundamental and unexpected role of neutrophils as the predominant phagocyte responsible for the clearance of apoptotic hepatic cells in the steady state. In contrast to the engulfment of dead cells by macrophages, neutrophils burrowed directly into apoptotic hepatocytes, a process we term perforocytosis, and ingested the effete cells from the inside. The depletion of neutrophils caused defective removal of apoptotic bodies, induced tissue injury in the mouse liver and led to the generation of autoantibodies. Human autoimmune liver disease showed similar defects in the neutrophil-mediated clearance of apoptotic hepatic cells. Hence, neutrophils possess a specialized immunologically silent mechanism for the clearance of apoptotic hepatocytes through perforocytosis, and defects in this key housekeeping function of neutrophils contribute to the genesis of autoimmune liver disease.

physiology↗

bioRxiv2023

Genetic timeline of human brain and cognitive traits

Human evolution is characterised by extensive changes of body and brain, with perhaps one of the core developments being the fast increase in cranial capacity and brain volume. Paleontological records are the most direct method to study such changes, but they can unfortunately provide a limited view of how soft traits such as brain function and cognitive abilities have evolved in humans. A potential complementary approach is to identify when particular genetic variants associated with human phenotypes (such as height, body mass index, intelligence, and also disease) have emerged in the 6-7 million years since we diverged from chimpanzees. In this study, we combine data from genome-wide association studies on human brain and cognitive traits with estimates of human genome dating. We systematically analyse the temporal emergence of genetic variants associated with modern-day human brain and cognitive phenotypes over the last five million years. Our analysis provides evidence that genetic variants related to neocortex structure (e.g., area, thickness; median evolutionary age = 400,170 years old), cognition (e.g., fluid intelligence; median age = 459,465), education (median age = 637,646), and psychiatric disorders (median age = 412,639) have emerged more recently in human evolution than expected by chance. In contrast, variants related to other physical traits, such as height (median age = 811,305) and body mass index (median age = 794,265), emerged relatively later. We further show that genes containing recent evolutionary modifications (from around 54,000 to 4,000 years ago) are linked to intelligence (P = 2 x 10-6) and neocortical surface area (P = 6.7 x 10-4), and that these genes tend to be highly expressed in cortical areas involved in language and speech (pars triangularis, P = 6.2 x 10-4). Elucidating the temporal dynamics of genetic variants associated with brain and cognition is another source of evidence to advance our understanding of human evolution.

genetics↗

bioRxiv2023

Variational graph encoders: a surprisingly effective generalist algorithm for holistic computer-aided drug design

1.While there has been significant progress in molecular property prediction in computer-aided drug design, there is a critical need to have fast and accurate models. Many of the currently available methods are mostly specialists in predicting specific properties, leading to the use of many models side-by-side that lead to impossibly high computational overheads for the common researcher. Henceforth, the authors propose a single, generalist unified model exploiting graph convolutional variational encoders that can simultaneously predict multiple properties such as absorption, distribution, metabolism, excretion and toxicity (ADMET), target-specific docking score prediction and drug-drug interactions. Considerably, the use of this method allows for state-of-the-art virtual screening with an acceleration advantage of up to two orders of magnitude. The minimisation of a graph variational encoders latent space also allows for accelerated development of specific drugs for targets with Pareto optimality principles considered, and has the added advantage of explainability.

bioinformatics↗

bioRxiv2023

Insm1 regulates the development of mTECs and immune tolerance

The Insm1 gene encodes a zinc finger protein with known functions in neuroendocrine cells and neurons. Here we characterized the expression and function of Insm1 in medullary thymic epithelial cells (mTECs). Insm1 is co-expressed with Aire in majority of Insm1 or Aire positive cells, while a few Insm1 positive cells did not express Aire. Mutation of Insm1 impair the expression of Aire and the generation of normal numbers of Aire-expressing mTECs during development. We detected downregulation of genes that expressed specifically in Aire-expressing mTEC and mimetic cells in Insm1 mutant mTECs. Conversely, when Insm1 was overexpressed in thymic epithelial cells in vivo, the size of the mTECs compartment was enlarged and the expression of Aire and genes expressed specifically in the neuroendocrine mimetic cells were increased. Mechanistically, Insm1 bound DNA in mTECs and the majority of the Insm1 binding sites were co-occupied by Aire. These Insm1 binding sites were enriched on super-enhancer regions and thus may contributed to remoted regulation. Both, mice with a thymus-specific mutation in Insm1 or nude mice transplanted with Insm1 mutant thymus, displayed autoimmune responses in multiple peripheral tissues. Together, our data demonstrate a role of Insm1 in development of mTECs and immune tolerance.

immunology↗

bioRxiv2023

RabbitVar: ultra-fast and accurate somatic small-variant calling on multi-core architectures

The continuous development of next-generation sequencing (NGS) technology has led to extensive and frequent use of genomic analysis in cancer research. The associated production of large-scale NGS datasets establishes the need for high-precision somatic variant calling methods that are highly optimized on commonly used hardware platforms. We present RabbitVar (https://github.com/LeiHaoa/RabbitVar), a scalable variant caller that can detect small somatic variants from paired tumor/normal NGS data on modern multi-core CPUs. Our approach combines candidate-finding and machine-learning-based filtering strategies with optimized data structures and multi-threading to achieve both high accuracy and efficiency. We have compared the performance of RabbitVar to leading state-of-the-art callers (Strelka2, Mutect2, NeuSomatic, VarDict, VarScan2) on real-world HCC1395 breast cancer datasets under different sequencing conditions and contamination rates. The evaluation results demonstrate that RabbitVar achieves highly competitive F1-scores when calling SNVs. Moreover, when calling the more challenging indel variants, it consistently achieves the highest F1-scores. RabbitVar is able to process a paired tumor and normal whole human genome sequencing datasets with 80x depth in less than 20 minutes on a 48-core workstation outperforming all other tested variant callers in terms of efficiency.

bioinformatics↗

bioRxiv2022

MYSM1 co-activates ERα action via histone and non-histone deubiquitination to confer antiestrogen resistance in breast cancer

Endocrine resistance is a crucial challenge in estrogen receptor alpha (ER)-positive breast cancer (BCa) therapy. Aberrant alteration in modulation of E2/ER signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Thus, identification the efficient ER cofactor remains necessary for finding a potential therapeutic target for endocrine resistance. Herein, we have demonstrated that Myb like, SWIRM and MPN domains 1 (MYSM1) as a histone deubiquitinase is a novel ER co-activator with established Drosophila experimental model. Our results showed that MYSM1 participated in up-regulation of ER action via histone and non-histone deubiquitination. We provided the evidence to show that MYSM1 was involved in maintenance of ER stability via ER deubiquitination. Furthermore, silencing MYSM1 induced enhancement of histone H2A ubiquitination as well as reduction of histone H3K4me3 and H3Ac levels at cis regulatory elements on promoter of ER-regulated gene. In addition, MYSM1 depletion attenuated cell proliferation/growth in BCa-derived cell lines and xenograft models. Knockdown of MYSM1 increased the sensitivity of antiestrogen agents in BCa cells. MYSM1 was highly expressed in clinical BCa samples, especially in aromatase inhibitor (AI) non-responsive tissues. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ER action and provide a potential therapeutic target for endocrine resistance in BCa.

cell biology↗

bioRxiv2022

Gap-free nuclear and mitochondrial genomes of Fusarium verticillioides strain HN2

Fusarium ear rot (FER) and Fusarium stalk rot (FSR) caused by the filamentous fungus Fusarium verticillioides have become increasingly serious around the world. Additionally, fumonisins produced by F. verticillioides threaten food and feed security. By adding the contribution of genomic resources to better understand the pathosystem including the mechanisms of F. verticillioides-maize interactions, and further improving the quality of the F. verticillioides genome, the gap-free nuclear genome and mitochondrial genome of F. verticillioides strain HN2 were sequenced and assembled. Using Oxford Nanopore long reads and next-generation sequencing short reads, the final 42.81-Mb genome was assembled into 12 contigs (N50 = 4.16-Mb). A total of 13,466 protein-coding genes were annotated, including 1,076 secreted proteins that contain 342 candidate effectors. In addition, we assembled the complete 53,764 bp mitochondrial genome. F. verticillioides strain 7600 genome assemblies are fragmented and high-quality reference genomes were needed. The genomes presented here will serve as an important resource for F. verticillioides research.

genomics↗

bioRxiv2022

Bovine blastocyst like structures derived from stem cell cultures

Understanding blastocyst formation and implantation is critical for improving farm animal reproduction but is hampered by a limited supply of embryos. We developed an efficient method to generate bovine blastocyst-like structures (termed blastoids) via the assembly of trophoblast stem cells and expanded potential stem cells. Bovine blastoids resemble blastocysts in morphology, cell composition, single-cell transcriptomes, and represent an accessible in vitro model for studying bovine embryogenesis.

developmental biology↗