Biology subjects

Liu, Y.

Publications and source records attributed to Liu, Y..

At least 1,441 records · Page 80Linked to original sources

bioRxiv2023

Integrating large-scale meta-GWAS and PigGTEx resources to decipher the genetic basis of complex traits in pig.

Understanding the molecular and cellular mechanisms that underlie complex traits in pigs is crucial for enhancing their genetic improvement program and unleashing their substantial potentials in human biomedicine research. Here, we conducted a meta-GWAS analysis for 232 complex traits with 28.3 million imputed whole-genome sequence variants in 70,328 individuals from 14 pig breeds. We identified a total of 6,878 genomic regions associated with 139 complex traits. By integrating with the Pig Genotype-Tissue Expression (PigGTEx) resource, we systemically explored the biological context and regulatory circuits through which these trait-associated variants act and finally prioritized 16,664 variant-gene-tissue-trait circuits. For instance, rs344053754 regulates the expression of UGT2B31 in the liver by affecting the activity of regulatory elements and ultimately influences litter weight at weaning. Furthermore, we investigated the conservation of genetic and regulatory mechanisms underlying 136 human traits and 232 pig traits. Overall, our multi-breed meta-GWAS in pigs provides invaluable resources and novel insights for understanding the regulatory and evolutionary mechanisms of complex traits in both pigs and humans.

genetics↗

bioRxiv2023

Data-driven optimization yielded a highly-efficient CRISPR/Cas9 system for gene editing in Arabidopsis

The CRISPR/Cas9 technology is widely used for plant gene editing. In Arabidopsis, the early CRISPR/Cas9 systems using constitutive promoters to drive Cas9 expression usually have low heritable mutation efficiencies in the T1 generation. Germ cell-specific or cell division-specific promoters, like EC1.2en-EC1.1p fusion, YAO and CDC45, have been used as alternatives to direct Cas9 expression, but the efficiency of getting nonchimeric mutations is still not high. To further improve gene editing efficiency, we used gene co-expression network analysis to identify NUC1 as a candidate promoter for driving Cas9 expression. NUC1 has expression patterns similar to YAO, but expresses at a much higher level. We constructed a CRISPR/Cas9 system pHY07 that uses the NUC1 promoter to drive Cas9 and carries the mCherry protein as a fluorescent marker for selecting transgenic seeds. Using this system to edit the GL2 gene, we obtained apparently nonchimeric mutations in 55% of the T1 transgenic plants. Among the Cas9-free T2 plants 99% harbored mutations that are stably inherited from the previous generation. Therefore, our system exhibited extremely high editing efficiency, and through fluorescent screening of transgenic seeds, it become easy to obtain Cas9-free and stable genetic mutants in the T2 generation.

plant biology↗

bioRxiv2023

Overriding Mendelian inheritance in Arabidopsis with a CRISPR toxin-antidote gene drive that impairs pollen germination

Synthetic gene drives, inspired by natural selfish genetic elements, present transformative potential for disseminating traits that benefit humans throughout wild populations, irrespective of potential fitness costs. Here, we constructed a gene drive system called CRISPR-Assisted Inheritance utilizing NPG1 (CAIN), which employs a toxin-antidote mechanism in the male germline to override Mendelian inheritance in plants. Specifically, a gRNA-Cas9 cassette targets the essential No Pollen Germination 1 (NPG1) gene, serving as the toxin to block pollen germination. A recoded, CRISPR-resistant copy of NPG1 serves as the antidote, providing rescue only in pollen cells that carry the drive. To limit potential consequences of inadvertent release, we used self-pollinating Arabidopsis thaliana as a model. The drive demonstrated a robust 88-99% transmission rate over two successive generations, producing minimal resistance alleles that are unlikely to inhibit drive spread. Our study provides a strong basis for rapid genetic modification or suppression of outcrossing plant populations.

evolutionary biology↗

bioRxiv2023

Oligodendroglial precursors orchestrate immune network instigating early demyelination in experimental autoimmune encephalomyelitis

The immunomodulatory cellular network that triggers early inflammation and demyelination, the key steps in multiple sclerosis (MS) pathogenesis remains poorly characterized. Here, we demonstrate that overactivation of Wnt pathway promotes pathological transformation of oligodendrocyte precursor cells (OPCs) to replicate pathological OPCs in human MS. In mouse experimental autoimmune encephalomyelitis (EAE), pathological OPCs attract CD4+ T-helper 1 (Th1) cells into the spinal cord and brain through CC-chemokine ligand 4 (CCL4), whilst OPCs cooperate with Th1 cells inducing transformation of cytotoxic macrophages that execute early demyelination. Simultaneously, Th1 cells and cytotoxic macrophages upregulate Wnt signaling and CCL4 expression in OPCs, thus exerting positive feedback onto the OPC-immune cascade and establishing a vicious cycle propagating EAE pathogenesis. Breaking this cascade by targeting CCL4 reduces immune cell infiltration, alleviates demyelination, and attenuates EAE severity. Our findings demonstrate a closely coordinated network of OPCs and immune cells therefore providing an alternative insight into MS pathophysiology.

neuroscience↗

bioRxiv2023

Reduced nephron endowment in the common Six2-TGCtg mouse line is due to Six3 misexpression by aberrant enhancer-promoter interactions in the transgene

Lifelong kidney function relies on the complement of nephrons generated during mammalian development from a mesenchymal nephron progenitor cell (NPC) population. Low nephron endowment confers increased susceptibility to chronic kidney disease. We asked whether reduced nephron numbers in the popular Six2TGC transgenic mouse line1 was due to disruption of a regulatory gene at the integration site or to ectopic expression of a gene(s) contained within the transgene. Targeted locus amplification identified integration of the Six2TGC transgene within an intron of Cntnap5a on chr1. We generated Hi-C datasets from NPCs isolated from the Six2TGCtg/+ mice, the Cited1CreERT2/+control mice, and the Six2TGCtg/+;Tsc1+/Flox,2 mice that exhibited restored nephron number compared with Six2TGCtg/+mice, and mapped the precise integration of Six2TGC and Cited1CreERT2transgenes to chr1 and chr14, respectively. No changes in topology, accessibility, or expression were observed within the 50-megabase region centered on Cntnap5a in Six2TGCtg/+ mice compared with control mice. By contrast, we identified an aberrant regulatory interaction between a Six2 distal enhancer and the Six3 promoter contained within the transgene. Increasing the Six2TGCtg to Six2 locus ratio or removing one Six2 allele in Six2TGCtg/+ mice, caused severe renal hypoplasia. Furthermore, CRISPR disruption of Six3 within the transgene (Six2TGC{Delta}Six3CT) restored nephron endowment to wildtype levels and abolished the stoichiometric effect. Data from genetic and biochemical studies together suggest that in Six2TGC, SIX3 interferes with SIX2 function in NPC renewal through its C-terminal domain. SignificanceUsing high-resolution chromatin conformation and accessibility datasets we mapped the integration site of two popular transgenes used in studies of nephron progenitor cells and kidney development. Aberrant enhancer-promoter interactions drive ectopic expression of Six3 in the Six2TGCtgline which was correlated with disruption of nephrogenesis. Disruption of Six3 within the transgene restored nephron numbers to control levels; further genetic and biochemical studies suggest that Six3 interferes with Six2-mediated regulation of NPC renewal.

developmental biology↗

bioRxiv2023

Single nuclei chromatin accessibility and transcriptomic map of breast tissues of women of diverse genetic ancestry

Single nuclei analysis is allowing robust classification of cell types in an organ that helps to establish relationships between cell-type specific gene expression and chromatin accessibility status of gene regulatory regions. Using breast tissues of 92 healthy donors of various genetic ancestry, we have developed a comprehensive chromatin accessibility and gene expression atlas of human breast tissues. Integrated analysis revealed 10 distinct cell types in the healthy breast, which included three major epithelial cell subtypes (luminal hormone sensing, luminal adaptive secretory precursor, and basal-myoepithelial cells), two endothelial subtypes, two adipocyte subtypes, fibroblasts, T-cells, and macrophages. By integrating gene expression signatures derived from epithelial cell subtypes with spatial transcriptomics, we identify specific gene expression differences between lobular and ductal epithelial cells and age-associated changes in epithelial cell gene expression patterns and signaling networks. Among various cell types, luminal adaptive secretory cells and fibroblasts showed genetic ancestry dependent variability. A subpopulation of luminal adaptive secretory cells with alveolar progenitor (AP) cell state were enriched in Indigenous American (IA) ancestry and fibroblast populations were distinct in African ancestry. ESR1 expression pattern was distinctly different in cells from IA compared to the rest, with a high level of ESR1 expression extending to AP cells and crosstalk between growth factors and Estrogen Receptor signaling being evident in these AP cells. In general, cell subtype-specific gene expression did not uniformly correlate with cell-specific chromatin accessibility, suggesting that transcriptional regulation independent of chromatin accessibility governs cell type-specific gene expression in the breast.

cancer biology↗

bioRxiv2023

Segzoo: a turnkey system that summarizes genome annotations

Segmentation and automated genome annotation (SAGA) techniques, such as Segway and ChromHMM, assign labels to every part of the genome, identifying similar patterns across multiple genomic input signals. Inferring biological meaning in these patterns remains challenging. Doing so requires a time-consuming process of manually downloading reference data, running multiple analysis methods, and interpreting many individual results. To simplify these tasks, we developed the turnkey system Segzoo. As input, Segzoo only requires a genome annotation file in browser extensible data (BED) format. It automatically downloads the rest of the data required for comparisons. Segzoo performs analyses using these data and summarizes results in a single visualization. Availability and ImplementationSource code for Python [≥]3.7 on Linux freely available for download at https://github.com/hoffmangroup/segzoo under the GNU General Public License (GPL) version 2. Segzoo is also available in the Bioconda package segzoo: https://anaconda.org/bioconda/segzoo.

bioinformatics↗

bioRxiv2023

Spatial transcriptomics of peach and nectarine elucidates the mechanism underlying fruit trichome development

Peach (Prunus persica) is an economically significant fruit-bearing tree. The trichomes of peach fruits are essential for their growth and development by playing a protective role against abiotic stresses, such as intense ultraviolet (UV) light, high temperature, cold-induced stress, and biotic stresses, such as pests and disease infestation. However, the mechanism underlying trichome development in peach fruits is unknown. Therefore, spatial transcriptome sequencing technology was used to compare the transcriptomic information seven days after flowering (DAF) of peach and nectarine fruits at an ultra-high resolution. The results revealed significant variations in how fruits at the early development stage responded to stress exposure. Comparatively, nectarine response to stress was significantly magnified than peach. Notably, a novel trichome-related marker gene, Prupe.7G196500, was identified in peach, which showed a robust function in response to jasmonic acid and wounding. Further, the Prupe.7G196500pro::GUS construct was found to specifically expressed in the trichomes of the true leaves of 10-day-old Arabidopsis thaliana (Arabidopsis) seedlings and induced by drought treatment. Finally, gain-of-function analysis showed that Prupe.7G196500 promoted trichomes development. In conclusion, this study identified the cell types and novel marker genes associated with peach fruit. The role of Prupe.7G196500 in positively regulating trichome development was also characterized, thereby laying the foundation for analyzing the mechanism involved in trichome development in peach fruits.

developmental biology↗

bioRxiv2023

Identifying key underlying regulatory networks and predicting targets of orphan C/D box SNORD116 snoRNAs in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder characterized principally by initial symptoms of neonatal hypotonia and failure-to-thrive in infancy, followed by hyperphagia and obesity. It is well established that PWS is caused by loss of paternal expression of the imprinted region on chromosome 15q11-q13. While most PWS cases exhibit megabase-scale deletions of the paternal chromosome 15q11-q13 allele, several PWS patients have been identified harboring a much smaller deletion encompassing primarily SNORD116. This finding suggests SNORD116 is a direct driver of PWS phenotypes. The SNORD116 gene cluster is composed of 30 copies of individual SNORD116 C/D box small nucleolar RNAs (snoRNAs). Many C/D box snoRNAs have been shown to guide chemical modifications of other RNA molecules, often ribosomal RNA (rRNA). However, SNORD116 snoRNAs are termed orphans because no verified targets have been identified and their sequences show no significant complementarity to rRNA. It is crucial to identify the targets and functions of SNORD116 snoRNAs because all reported PWS cases lack their expression. To address this, we engineered two different deletions modelling PWS in two distinct human embryonic stem cell (hESC) lines to control for effects of genetic background. Utilizing an inducible expression system enabled quick, reproducible differentiation of these lines into neurons. Systematic comparisons of neuronal gene expression across deletion types and genetic backgrounds revealed a novel list of 42 consistently dysregulated genes. Employing the recently described computational tool snoGloBe, we discovered these dysregulated genes are significantly enriched for predicted SNORD116 targeting versus multiple control analyses. Importantly, our results showed it is critical to use multiple isogenic cell line pairs, as this eliminated many spuriously differentially expressed genes. Our results indicate a novel gene regulatory network controlled by SNORD116 is likely perturbed in PWS patients.

genetics↗

bioRxiv2023

Base Excision Repair Pathway Regulates Transcription-Replication Conflicts in Pancreatic Ductal Adenocarcinoma

Oncogenic mutations (such as in KRAS) can dysregulate transcription and replication leading to transcription conflicts (TRCs). Unresolved TRCs can cause lethal DNA damage. Here, we sought to investigate the oncogene dependency of TRCs and TRC regulatory pathways in pancreatic ductal adenocarcinoma (PDAC). Human PDAC demonstrated 30-120-fold higher levels of TRC genomic signatures compared to breast, colon and lung cancer (p<0.001). TRCs were significantly enriched in human PDAC cells (Panc-1, BxPC3, MiaPaca2) compared to immortalized human pancreatic ductal epithelial (HPNE). Ectopic oncogenic KRAS(G12D) in HPNE cells enhanced TRCs, and TRC-related DNA:RNA hybrids (R-loops). Inhibition of KRAS or downstream effectors abrogated TRCs in Panc1 and MiaPaca2 cells. An siRNA screen identified several factors in the base-excision repair pathway as regulators of TRCs. In pharmacologic validation, inhibitors of APE1 endonuclease in BER pathway (Methoxyamine and CRT) enhanced TRCs. Mechanistic studies revealed that BER pathway inhibition severely altered RNA polymerase II dynamics at nascent DNA; causing RNAPII trapping and contributing to enhanced TRCs. The ensuing DNA damage activated Chk2-ATR pathway but not Chk1-ATM pathway. Co-treatment with ATR inhibitor (VX970) and BER inhibitor (methoxyamine) at clinically relevant doses, synergistically enhanced DNA damage and reduced cell proliferation in PDAC cells. The study uncovers a novel role of BER pathway defects and oxidative DNA damage in promoting TRCs. Our studies provide mechanistic insights into the regulation of TRCs in PDAC which has implications for genome instability and therapy in PDAC.

cancer biology↗

bioRxiv2023

Prognostic implications and biological roles of EMT-related lncRNAs in lung squamous cell carcinoma: an in-depth analysis utilizing a novel prognostic signature and classification system

BackgroundLung squamous cell carcinoma (LUSC) represents a major subtype of non-small cell lung cancer (NSCLC), a leading contributor to cancer-related mortality. Epithelial-mesenchymal transition (EMT)-associated genes have been implicated in poor survival and metastatic gene expression in LUSC. Long non-coding RNAs (lncRNAs) are known to facilitate tumor progression and metastasis via EMT regulation. However, the prognostic significance and biological functions of EMT-associated lncRNAs in LUSC remain to be elucidated. MethodsIn this study, we aimed to develop an EMT-related lncRNA prognostic signature (EMT-LPS) utilizing RNA transcription data from LUSC patients in The Cancer Genome Atlas (TCGA) database, along with corresponding clinical characteristics. Kaplan-Meier analysis, receiver operating characteristic (ROC) curves, and Cox regression were employed to validate and assess the model. Furthermore, we confirmed the independent prognostic value of key genes in EMT-LPS using Gene Expression Profiling Interactive Analysis (GEPIA). Additionally, we proposed a novel LUSC classification system based on EMT-related lncRNA expression patterns, evaluating the prognostic profile, tumor microenvironment, and immunotherapy sensitivity of each subtype. ResultsA prognostic signature comprising twelve genes was constructed, and patients were stratified into high and low-risk groups according to their risk scores. Cox regression analysis revealed that the risk score served as an independent prognostic factor. A nomogram was generated to predict LUSC patient survival rates. Distinct subtypes exhibited varying tumor purity, immunogenicity, and immunotherapy drug sensitivity. ConclusionsOur findings underscore the relevance of EMT-related lncRNAs in LUSC and their potential utility in guiding immunotherapy strategies. The EMT-LPS and novel LUSC typing scheme provide a new perspective for understanding the biological functions and prognostic role of EMT-related lncRNAs in LUSC.

bioinformatics↗

bioRxiv2023

Daptomycin forms a stable complex with phosphatidylglycerol for selective uptake to bacterial membrane

Daptomycin is a potent lipopeptide antibiotic used in the treatment of live-threatening Gram-positive infections, but the molecular mechanism of its interaction with bacterial membrane remains unclear. Here we show that this interaction is divided into two stages, of which the first is a fast and reversible binding of the drug to phospholipid membrane in milliseconds and the second is a slow and irreversible insertion into membrane in minutes, only in the presence of the bacteria-specific lipid phosphatidylglycerol, to a saturating point where the ratio of the drug to phosphatidylglycerol is 1:2. Fluorescence-based titration showed that the antibiotic simultaneously binds two molecules of phosphatidylglycerol with a nanomolar binding affinity in the presence of calcium ion. The resulting stable complex is easily formed in a test tube and readily isolated from the membrane of drug-treated bacterial cells, strongly supporting a unique drug uptake mechanism in which daptomycin forms a stable multi-component complex with calcium and phosphatidylglycerol. Revelation of this novel uptake mechanism provides fresh insights into the mode of action of daptomycin and paves the way to new strategies to attenuate resistance to the drug.

biochemistry↗

bioRxiv2023

A telomere-to-telomere genome assembly of Zhonghuang 13, a widely-grown soybean variety from the original center of Glycine max

Soybean (Glycine max) stands as a globally significant agricultural crop, and the comprehensive assembly of its genome is of paramount importance for unraveling its biological characteristics and evolutionary history. Nevertheless, previous soybean genome assemblies have harbored gaps and incompleteness, which have constrained in-depth investigations into soybean. Here, we present the first Telomere-to-Telomere (T2T) assembly of the Chinese soybean cultivar "Zhonghuang 13" (ZH13) genome, termed ZH13-T2T, utilizing PacBio Hifi and ONT ultralong reads. We employed a multi-assembler approach, integrating Hifiasm, NextDenovo, and Canu, to minimize biases and enhance assembly accuracy. The assembly spans 1,015,024,879 bp, effectively resolving all 393 gaps that previously plagued the reference genome. Our annotation efforts identified 50,564 high-confidence protein-coding genes, 707 of which are novel. ZH13-T2T revealed longer chromosomes, 421 not-aligned regions (NARs), 112 structure variations (SVs), and a substantial expansion of repetitive element compared to earlier assemblies. Specifically, we identified 25.67 Mb of tandem repeats, an enrichment of 5S and 48S rDNAs, and characterized their genotypic diversity. In summary, we deliver the first complete Chinese soybean cultivar T2T genome. The comprehensive annotation, along with precise centromere and telomere characterization, as well as insights into structural variations, further enhance our understanding of soybean genetics and evolution.

plant biology↗

bioRxiv2023

Neuroprotective Mechanism of Ribisin A on H 2 O 2 -induced PC12 cell injury model

Ribisin A has been shown to have neurotrophic activity. The aim of this study was to evaluate the neuroprotective effect of Ribisin A on injured PC12 cells and elucidate its mechanism. In this project, PC12 cells were induced by H2O2 to establish an injury model. After treatment with Ribisin A, the neuroprotective mechanism of Ribisin A was investigated by methyl tetrazolium (MTT) assay, Enzyme-linked immunosorbent assay (ELISA), flow cytometric analysis, fluorescent probe analysis, and western blot. We found that Ribisin A decreased the rate of lactate dehydrogenase (LDH) release, increased cellular superoxide dismutase (SOD) activity, decreased the levels of tumor necrosis factor- (TNF-), interleukin-6 (IL-6), Ca2+ expression and reactive oxygen species (ROS). Moreover, Ribisin A significantly increased mitochondrial membrane potential (MMP) and inhibited apoptosis of PC12 cells. Meanwhile, Ribisin A activated the phosphorylation of ERK1/2 and its downstream molecule CREB by upregulating the expression of Trk A and Trk B, the upstream molecules of the ERK signaling pathway. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/559840v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@ff9604org.highwire.dtl.DTLVardef@1d1ee75org.highwire.dtl.DTLVardef@17e4441org.highwire.dtl.DTLVardef@b347c4_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

Mechanisms analysis for Formononetin counteracted-Osimertinib resistance in Non-small-cell lung cancer cells: from the insight into the gene transcriptional level

BackgroundsOsimertinib resistance in Non-Small-Cell Lung Cancers (NSCLC) is a difficult problem to be solved in clinic. Formononetin is one of the main isoflavone components, which has strong anti-cancer effects in NSCLC. However, the potential effects and the mechanisms of Formononetin to counteract the Osimertinib resistant in NSCLC is remain to be uncovered. MethodsOsimertinib-resistant NSCLC cell line (H1975_OR) was generated by increasingly adding of Osimertinib in H1975 cell culture medium. The Formononetin was used to induce H1975_OR cell apoptosis an to inhibit cell proliferation and clonal formation. The RNA-sequencing was used to study the potential mechanisms for Formononetin to counteract the Osimertinib resistant in NSCLC. ResultsFormononetin could significantly induced cell apoptosis, whereas, dramatically inhibited cell proliferation and clinal formation in H1975_OR cells. Formononetin induced tremendous alterations of gene expression in H1975_OR cells and these genes can be clustered into unique GO, KEGG and GSEA pathways. ConclusionOur results preliminarily uncovered the underlying mechanisms for Formononetin counteracted Osimertinib-resistance in NSCLC cells and provided a potential treatment method for Osimertinib resistant NSCLC patients.

cancer biology↗

bioRxiv2023

Prothoracicotropic hormone controls female sexual receptivity through the function of ecdysone in pC1 neurons of Drosophila

Female sexual receptivity is essential for reproduction of a species. Neuropeptides play the main role in regulating female receptivity. However, whether neuropeptides regulate female sexual receptivity during the neurodevelopment is unknown. Here we found the peptide hormone prothoracicotropic hormone (PTTH), which belongs to the insect PG axis, negatively regulated virgin female receptivity through ecdysone during neurodevelopment in Drosophila melanogaster. We identified PTTH neurons as doublesex-positive neurons, they regulated virgin female receptivity before the metamorphosis during the 3rd-instar larval stage. PTTH deletion resulted in the increased EcR-A expression in the whole newly formed prepupae. Furthermore, the ecdysone receptor EcR-A in pC1 neurons positively regulated virgin female receptivity during metamorphosis. The decreased EcR-A in pC1 neurons induced abnormal morphological development of pC1 neurons without changing neural activity. Among all subtypes of pC1 neurons, the function of EcR-A in pC1b neurons was necessary for virgin female copulation rate. These suggested that the changes of synaptic connections between pC1b and other neurons decreased female copulation rate. Moreover, female receptivity significantly decreased when the expression of PTTH receptor Torso was reduced in pC1 neurons. This suggested that PTTH not only regulates female receptivity through ecdysone but also through affecting female receptivity associated neurons directly. The PG axis has similar functional strategy as the HPG axis in mammals to trigger the juvenile-adult transition. Our work suggests a general mechanism underlying which the neurodevelopment during maturation regulates female sexual receptivity.

neuroscience↗

bioRxiv2023

Changes in the urinary proteome of rats after short-term intake of magnesium threonate

Magnesium is an important mineral in living organisms and has multiple functions in the human body, wherein it plays an important therapeutic and preventive role in a variety of diseases. In the present study, urine samples of rats before and after gavage of magnesium threonate were collected, and the urinary proteome was identified using the LC-MS/MS technique and analyzed using various databases. The results illustrated that the urinary proteome of rats was significantly altered after short-term intake of magnesium supplements and that the differential proteins and the biological functions were related to magnesium. This study innovatively establishes a method to study nutrients from the perspective of urine proteomics. This work demonstrates that the urinary proteome is capable of reflecting the effects of nutrient intake on the organism in a more systematic and comprehensive manner and has the potential to provide clues for clinical nutrition research and practice.

biochemistry↗

bioRxiv2023

GeneCompass: Deciphering Universal Gene Regulatory Mechanisms with Knowledge-Informed Cross-Species Foundation Model

Deciphering the universal gene regulatory mechanisms in diverse organisms holds great potential to advance our knowledge of fundamental life process and facilitate research on clinical applications. However, the traditional research paradigm primarily focuses on individual model organisms, resulting in limited collection and integration of complex features on various cell types across species. Recent breakthroughs in single-cell sequencing and advancements in deep learning techniques present an unprecedented opportunity to tackle this challenge. In this study, we developed GeneCompass, the first knowledge-informed, cross-species foundation model pre-trained on an extensive dataset of over 120 million single-cell transcriptomes from human and mouse. During pre-training, GeneCompass effectively integrates four types of biological prior knowledge to enhance the understanding of gene regulatory mechanisms in a self-supervised manner. Fine-tuning towards multiple downstream tasks, GeneCompass outperforms competing state-of-the-art models in multiple tasks on single species and unlocks new realms of cross-species biological investigation. Overall, GeneCompass marks a milestone in advancing knowledge of universal gene regulatory mechanisms and accelerating the discovery of key cell fate regulators and candidate targets for drug development.

bioinformatics↗