Biology subjects

Dong, J.

Publications and source records attributed to Dong, J..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

SIRT5-mediated GLS and GDH desuccinylation attenuates autophagy in MAC-T cells induced by ammonia

Our previous research revealed that NH3 regulated autophagy dependent on SIRT5 in MAC-T cells. Interestingly, SIRT5 reduced the content of NH3 and glutamate by inhibiting GLS activity, ADP/ATP value also declined. In this study, SIRT5 interacted with endogenous GLS and GDH, and had no effect on endogenous GLS and GDH expression. SIRT5 declined significantly the succinylation levels of GLS and GDH, and further reduced the enzymatic activity of GLS and GDH. SIRT5 declined the glutamine metabolism, which attenuated ammonia release in MAC-T cells, accompanying with cellular autophagy decline, reducing the formation of autophagosome. Deletion of SIRT5 increased the content of NH3 and glutamate, as well as promotes autophagy, which could be alleviated by SIRT5 overexpression. SIRT5 KO was associated with increased succinylation and activity of GLS and GDH, as well as autophagy response in MAC-T cells. Furthermore, SIRT5 promoted the maintenance of mitochondria homeostasis. Mechanistically, SIRT5 modulated the succinylation levels and enzymatic activities of GLS and GDH in mitochondria and promoted the maintenance of mitochondria homeostasis, further attenuating ammonia-stimulated autophagy in MAC-T cells. HighlightsO_LISIRT5 catalyzed lysine desuccinylation of GLS and GDH. C_LIO_LIGLS and GDH enzymatic activity were enhanced by lysine succinylation. C_LIO_LIGLS and GDH were required for SIRT5 to regulate ammonia-induced cellular autophagy. C_LIO_LISIRT5 promoted the maintenance of mitochondrial homeostasis C_LI

physiology↗

bioRxiv2024

ER stress-induced TREM2 downregulation exacerbates platelet activation and myocardial infarction in patients with coronary artery disease

Coronary artery disease (CAD) is characterized by the chronic immune-inflammation, excessive endoplasmic reticulum (ER) stress, and platelet hyperactivity; however, whether there is a signaling hub linking these events remains unclear. Here, we identified that triggering receptor expressed on myeloid cells 2 (TREM2), an important pattern recognition receptor of the innate immune system, may serve as one such hub. We found that platelets expressed TREM2 and platelets from CAD patients had decreased TREM2 expression compared to healthy subjects. Decreased TREM2 is associated with platelet hyperactivity in CAD patients. This decrease could be due to excessive ER stress, which downregulated TREM2 through the CHOP-C/EBP axis. Loss of TREM2 not only enhanced platelet activation in response to ADP, collagen, and collagen-related peptide (CRP), but also amplified the platelet inflammatory response. Loss of TREM2 exacerbated mouse mesenteric arterial thrombosis and aggravated experimental myocardial infarction (MI). Moreover, a TREM2-activating antibody inhibited platelet activation, alleviated arterial thrombosis and pulmonary embolism. In addition, TREM2-activating antibody exhibited cardioprotective roles against experimental MI and reduced the inflammatory burden. Mechanistically, TREM2/DAP12/SHIP1 axis negatively regulated platelet activation through reducing PIP3 levels and inhibiting Akt phosphorylation. We also provided evidence supporting sphingosine-1-phospage (S1P) as a physiological agonist of TREM2. In summary, we find that TREM2 connects chronic immune-inflammation, excessive ER stress, and platelet hyperactivity in CAD patients. Downregulating TREM2 by ER stress exacerbates platelet activation and amplifies inflammation response in patients with CAD. TREM2-activating antibodies may have therapeutic potential for CAD patients. Key PointsO_LIPlatelets from CAD patients have decreased TREM2 expression, which is caused by ER stress and associated with platelet hyperactivity. C_LIO_LIS1P-TREM2-SHIP1 pathway inhibits platelet activation, alleviates arterial thrombosis, and exhibits cardioprotective roles against experimental myocardial infarction. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/608887v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1e21f2eorg.highwire.dtl.DTLVardef@6d427forg.highwire.dtl.DTLVardef@128af74org.highwire.dtl.DTLVardef@16f48c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOVisual Abstract.C_FLOATNO Downregulation of platelet TREM2 caused by ER stress in CAD patients leads to platelet hyperactivity and aggravates myocardial ischemia, which is rescued by TREM2-activating antibody. Excessive ER stress in CAD upregulates CHOP, which dimerizes with C/EBP, a transcription factor of TREM2, decreases TREM2 transcription and expression in megakaryocytes and further in platelets. TREM2/DAP12/SHIP1/Akt pathway negatively regulates platelet activation; decreased TREM2 thus aggravates platelet hyperactivity, inflammation, and myocardial infarction, which can be rescued by TREM2 activation including antibody or the small molecule agonist. Physiologically, S1P released from platelet granules is an endogenous agonist of TREM2. C_FIG

pharmacology and toxicology↗

bioRxiv2024

An emerging PB2-627 polymorphism increases the pandemic potential of avian influenza virus by breaking through ANP32 host restriction in mammalian and avian hosts

Alterations in the PB2-627 domain could substantially increase the risk of an avian influenza virus (AIV) pandemic. So far, a well-known mammalian mutation PB2-E627K has not been maintained in AIV in poultry, which limits the spread of AIVs from avian to humans. Here, we discovered a variant, PB2-627V, which combines the properties of avian-like PB2-627E and human-like PB2-627K, overcoming host restrictions and posing a risk for human pandemics. Specifically, by screening the global PB2 sequences, we discovered a new independent cluster with PB2-627V emerged in the 2010s, which is prevalent in various avian, mammalian, and human isolates of AIVs, including H9N2, H7N9, H3N8, 2.3.4.4b H5N1, and other subtypes. And, the increasing prevalence of PB2-627V in poultry is accompanied by a rise in human infection cases with this variant. Then we systematically assessed its host adaptation, fitness, and transmissibility across three subtypes of AIVs (H9N2, H7N9, and H3N8) in different host models, including avian and human cells, chickens, mice, and ferrets where infections naturally occur. We found that PB2-627V facilitates AIVs to efficiently infect and replicate in chickens and mice by utilizing both avian- and human-origin ANP32A proteins. Importantly, and like PB2-627K, PB2-627V promotes efficient transmission between ferrets through respiratory droplets. Deep sequencing in passaged chicken samples and transmitted ferret samples indicates that PB2-627V remains stable across the two distinct hosts and has a high potential for long-term prevalence in avian species. Therefore, the mutation has the ability to continue spreading among poultry and can also overcome the barrier between birds and humans, greatly enhancing the likelihood of AIVs infecting humans. Given the escalating global spread of AIVs, it is crucial to closely monitor influenza viruses carrying PB2-627V to prevent a pandemic.

microbiology↗

bioRxiv2024

Patch and matrix striatonigral neurons differentially regulate locomotion

Spiny projection neurons (SPNs) in the dorsal striatum play crucial roles in locomotion control and value-based decision-making. SPNs, which include both direct-pathway striatonigral and indirect-pathway striatopallidal neurons, can be further classified into subtypes based on distinct transcriptomic profiles and cell body distribution patterns. However, how these SPN subtypes regulate spontaneous locomotion in the context of environmental valence remains unclear. Using Sepw1-Cre transgenic mice, which label a specific SPN subtype characterized by a patchy distribution of cell bodies in the dorsal striatum, we found that these patchy striatonigral neurons constrain motor vigor in response to valence differentials. In a modified light/dark box test, mice exhibited differential walking speeds between the light and dark zones. Genetic ablation of these patchy SPNs disrupted restful slowing in the dark zone and increased zone discrimination by speed. In vivo recordings linked the activity of these neurons to zone occupancy, speed, and deceleration, with a specific role in mediating deceleration. Furthermore, chemogenetic activation of patchy SPNs--and optical activation of striatonigral neurons in particular--reduced locomotion and attenuated speed-based zone discrimination. These findings reveal that a subtype of patchy striatonigral neurons regulates implicit walking speed selection based on innate valence differentials.

neuroscience↗

bioRxiv2024

Terrestrial ecosystems enhance root zones in response to intensified drought

Adaptation of ecosystems root zones to climate change critically affects drought resilience and vegetation productivity. However, a global quantitative assessment of this mechanism is missing. Therefore, we analyzed observation-based data and found that the global average root zone water storage capacity (SR) increased by 11%, from 182 to 201 mm in 1982-2020. This increase amounts to 1657 billion m3 over the past four decades, affecting hydrological and ecological processes worldwide. SR increased in 9 out of 12 land cover types, while three relatively dry types experienced decreasing trends, potentially suggesting the crossing of ecosystem tipping points. Our results underscore the importance of considering root zone dynamics while analysing floods, droughts and carbon sequestration under climate change.

ecology↗

bioRxiv2024

Enhancing lipid production in plant cells through high-throughput genome editing and phenotyping via a scalable automated pipeline

Plant bioengineering is a time-consuming and labor-intensive process, with no guarantee of achieving the desired trait. Here we report a fast, automated, scalable, high-throughput pipeline for plant bioengineering (FAST-PB). FAST-PB achieves gene cloning, genome editing, and product characterization by integrating automated biofoundry engineering of callus and protoplast cells with single cell matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). We first demonstrate that FAST-PB can streamline the Golden Gate cloning process, with the capacity to construct 96 vectors in parallel. To prove the concept, using FAST-PB, we first found that PEG2050 significantly increases transfection efficiency by over 45%. To validate the pipeline, we established a reporter-gene-free method for CRISPR editing via mutation of HCF136, affecting cellular chlorophyll fluorescence. Next, we applied this pipeline for lipid production and found that diverse lipids were significantly enhanced up to sixfold through introducing multi-gene cassettes via CRISPR activation, and regenerated plant using this platform. Lastly, we harnessed FAST-PB to achieve high-throughput single-cell lipid profiling through the integration of MALDI-MS with the biofoundry, and differentiated engineered and unengineered cells using the single-cell lipidomics. These innovations massively increase the throughput of synthetic biology, genome editing, and metabolic engineering, and change what is possibly using single-cell metabolomics in plants.

synthetic biology↗

bioRxiv2024

ZNF143 binds DNA and stimulates transcription initiation to activate and repress direct target genes

Transcription factors bind to sequence motifs and act as activators or repressors. Transcription factors interface with a constellation of accessory cofactors to regulate distinct mechanistic steps to regulate transcription. We rapidly degraded the essential and ubiquitously expressed transcription factor ZNF143 to determine its function in the transcription cycle. ZNF143 facilitates RNA Polymerase initiation and activates gene expression. ZNF143 binds the promoter of nearly all its activated target genes. ZNF143 also binds near the site of genic transcription initiation to directly repress a subset of genes. Although ZNF143 stimulates initiation at ZNF143-repressed genes (i.e. those that increase expression upon ZNF143 depletion), the molecular context of binding leads to cis repression. ZNF143 competes with other more efficient activators for promoter access, physically occludes transcription initiation sites and promoter-proximal sequence elements, and acts as a molecular roadblock to RNA Polymerases during early elongation. The term context specific is often invoked to describe transcription factors that have both activation and repression functions. We define the context and molecular mechanisms of ZNF143-mediated cis activation and repression.

genomics↗

bioRxiv2024

SECRET-GWAS: Confidential Computing for Population-Scale GWAS

Genomic data from a single institution lacks global diversity representation, especially for rare variants and diseases. Confidential computing can enable collaborative GWAS without compromising privacy or accuracy, however, due to limited secure memory space and performance overheads previous solutions fail to support widely used regression methods. We present SECRET-GWAS: a rapid, privacy-preserving, population-scale, collaborative GWAS tool. We discuss several system optimizations, including streaming, batching, data parallelization, and reducing trusted hardware overheads to efficiently scale linear and logistic regression to over a thousand processor cores on an Intel SGX-based cloud platform. In addition, we protect SECRET-GWAS against several hardware side-channel attacks, including Spectre, using data-oblivious code transformations and optimized speculative load hardening. SECRET-GWAS is an open-source tool and works with the widely used Hail genomic analysis framework. Our experiments on Azures Confidential Computing platform demonstrate that SECRET-GWAS enables multivariate linear and logistic regression GWAS queries on population-scale datasets (one million patients, four million SNPs, 12 covariates) from ten independent sources in just 4.5 and 29 minutes, respectively.

bioinformatics↗

bioRxiv2024

Random adversarial threshold search enables automated DNA screening

Custom DNA synthesis underpins modern biology, but controlled genes in the wrong hands could threaten many lives and public trust in science. In .1992, a virology-trained mass murderer tried and failed to obtain physical samples of Ebola; today, viruses can be assembled from synthetic DNA fragments. Screening orders for controlled sequences is unreliable and expensive because current similarity search algorithms yield false alarms requiring expert human review. Exact-match search can achieve perfect specificity among short known sequences by detecting subsequences unique to controlled genes, but can be trivially evaded by incorporating mutations. Here we rescue exact-match search by additionally screening for predicted functional variants of pseudo-randomly chosen subsequences that arent found in known unregulated genes. To experimentally assess robustness, we protected nine windows from the M13 bacteriophage virus, then invited a "red team" to launch up to 21,000 attacks at each window and measure the fitness of their designed mutants. We identified defensible windows from regulated pathogens, built a test database that our experiments indicate will block 99.999% of functional attacks, and verified its sensitivity against redesigned enzymes. Exact-match search with functional variant prediction offers a promising way to safeguard biotechnology by automating DNA synthesis screening. SummarySearching for exact matches to pre-computed functional variants unique to controlled genes enables sensitive, secure, and automated DNA synthesis screening.

synthetic biology↗

bioRxiv2024

MegaKG: Toward an explainable knowledge graph for early drug development

In biomedical research, the utilization of Knowledge Graph (KG) has proven valuable in gaining deep understanding of various processes. In this study, we constructed a comprehensive biomedical KG, named as MegaKG, by integrating a total of 23 primary data sources, which finally consisted of 188, 844 nodes/entities and 9, 165, 855 edges/relations after stringent data processing. Such a massive KG can not only provide a holistic view of the entities of interest, but also generate insightful hypotheses on unknown relations by applying AI computations. We focused on the interplay of the key elements in drug development, such as genes, diseases and drugs, and aimed to facilitate practical applications that could benefit early drug development in industries. More importantly, we placed much emphasis on the exploitability of the predictions generated by MegaKG. This may greatly help researchers to assess the feasibility or design appropriate downstream validation experiments, making AI techniques more than just black-box models. In this regard, NBFNet was adopted, which combines the advantages of both traditional path-based methods and more recently developed GNN-based ones. Performance evaluation experiments indicated superior results by MegaKG. We also conducted real case studies to validate its practical utility in various scenarios, including target prediction, indication extension and drug repurposing. All these experiments highlighted the potential of MegaKG as a valuable tool in driving innovation and accelerating drug development in pharmaceutical industry.

bioinformatics↗

bioRxiv2024

mm2-gb: GPU Accelerated Minimap2 for Long Read DNA Mapping

Long-read DNA sequencing is becoming increasingly popular for genetic diagnostics. Minimap2 is the state-of-the-art long-read aligner. However, Minimap2s chaining step is slow on the CPU and takes 40-68% of the time especially for long DNA reads. Prior works in accelerating Minimap2 either lose mapping accuracy, are closed source (and not updated) or deliver inconsistent speedups for longer reads. We introduce mm2-gb which accelerates the chaining step of Minimap2 on GPU without compromising mapping accuracy. In addition to intra- and inter-read parallelism exploited by prior works, mm2-gb exploits finer levels of parallelism by breaking down high latency large workloads into smaller independent segments that can be run in parallel and leverages several strategies for better workload balancing including split-kernels and prioritized scheduling of segments based on sorted size. We show that mm2-gb on an AMD Instinct MI210 GPU achieves 2.57-5.33x performance improvement on long nanopore reads (10kb-100kb), and up to 1.87x performance gain on super long reads (100kb-300kb) compared to SIMD accelerated mm2-fast. mm2-gb is open-sourced and available at https://github.com/Minimap2onGPU/mm2-gb.

genomics↗

bioRxiv2024

Protein property prediction based on local environment by 3D equivariant convolutional neural networks

Predicting the properties of proteins is an important procedure in protein engineering. It determines the subspace of mutations for protein modifications, which is critical to the success of the project, but heavily relies on the knowledge and experience of scientists. In this study, we propose a novel deep 3D-CNN model, Eq3DCNN, specifically designed for local environment-related tasks in protein engineering. Eq3DCNN uses basic atom descriptors and their coordinates as inputs, utilizing customized data augmentations to enhance its training efficiency. To make the Eq3DCNN extracted features with more generalization capability, we incorporated a rotation equivariant module to get rotation invariant features. Using cross-validations with different data splitting strategies and under the scenarios of zero-shot predictions, we demonstrate that Eq3DCNN outperformed other 3D-CNN models in stability predictions, and also well-preformed on other prediction tasks, such as the binding pocket and the secondary structure predictions. Our results also identified the key factors that contribute to the models accuracy and the scope of its applications. These findings may help scientists in designing better mutation experiments and increasing the success rate in protein engineering.

bioinformatics↗

bioRxiv2024

Regulation of the aurantio-obtusin accumulation by StTCP4.1-mediated StDA1-StHDR1 module in Senna tora seeds

Senna tora (S. tora) is a commonly used Chinese medicinal plant due to the presence of the bioactive compounds anthraquinones in its mature seeds. Seed size is an important factor that affect S. tora yield quantity and quality. However, the mechanism regulating seed size and aurantio-obtusin biosynthesis in S.tora is still unclear. In this study, we identified the ubiquitin receptor StDA1 in S.tora that served as a negative regulator to seed formation and limited seed enlargement. Antisense overexpression of StDA1 led to larger seeds in S. tora and promoted the accumulation of aurantio-obtusin. In contrast, overexpression of StDA1 in S.tora resulted in a relative decrease in aurantio-obtusin accumulation. Moreover, StDA1 can directly bind to StHDR1and regulate its degradation through the 26S proteasome to regulate seed size and aurantio-obtusin accumulation. We also found that the StDA1-StHDR1 module is responsive to the MeJA via StTCP4.1, which in turn affects the accumulation of aurantio-obtusin. Overall, we have identified a protein complex that regulates the accumulation of aurantio-obtusin, StTCP4.1-StDA1-StHDR1, as a potential target for improving S.tora yield quantity and quality.

molecular biology↗

bioRxiv2024

Psilocybin Promotes Cell-Type-Specific Changes in the Orbitofrontal Cortex Revealed by Single-Nucleus RNA-seq

Recent clinical breakthroughs hold great promise for the application of psilocybin in the treatments of psychological disorders, such as depression, addiction, and obsessive-compulsive disorder. Psilocybin is a psychedelic whose metabolite, psilocin, is a 5-HT2A receptor agonist. Nevertheless, the underlying mechanisms for the effects of psilocybin on the brain are not fully illustrated, and cell type-specific and circuit effects of psilocybin are not fully understood. Here, we combined single-nucleus RNA-seq with functional assays to study the long-term effects of psilocybin on the orbitofrontal cortex (OFC), a brain region vulnerable to psychological disorders such as depression. We showed that a single dose of psilocybin induced long-term genetic and functional changes in neurons of the OFC, and excitatory and inhibitory neurons collectively reduced circuit activity of the brain region. Knockdown of 5-HT2A receptor in deep layer excitatory neurons abated psilocybin-induced functional changes and the anti-depressant effect. Together, these results showed the cell type-specific mechanisms of psilocybin and shed light on the brain region difference in the effect of psychedelics.

neuroscience↗

bioRxiv2024

Rab10 regulates neuropeptide release by maintaining Ca2+ homeostasis and protein synthesis

Dense core vesicles (DCVs) transport and release various neuropeptides and neurotrophins that control diverse brain functions, but the DCV secretory pathway remains poorly understood. Here, we tested a prediction emerging from invertebrate studies about the crucial role of the intracellular trafficking GTPase Rab10, by assessing DCV exocytosis at single-cell resolution upon acute Rab10 depletion in mature mouse hippocampal neurons, to circumvent potential confounding effects of Rab10s established role in neurite outgrowth. We observed a significant inhibition of DCV exocytosis in Rab10-depleted neurons, whereas synaptic vesicle exocytosis was unaffected. However, rather than a direct involvement in DCV trafficking, this effect was attributed to two ER-dependent processes, ER-regulated intracellular Ca2+ dynamics and protein synthesis. Gene ontology analysis of differentially expressed proteins upon Rab10 depletion identified substantial alterations in synaptic and ER/ribosomal proteins, including the Ca2+-pump SERCA2. In addition, ER morphology and dynamics were altered, ER Ca2+ levels were depleted and Ca2+ homeostasis was impaired in Rab10-depleted neurons. However, Ca2+ entry using a Ca2+ ionophore still triggered less DCV exocytosis. Instead, leucine supplementation, which enhances protein synthesis, largely rescued DCV exocytosis deficiency. We conclude that Rab10 is required for neuropeptide release by maintaining Ca2+ dynamics and regulating protein synthesis. Furthermore, DCV exocytosis appeared more dependent on (acute) protein synthesis than synaptic vesicle exocytosis.

neuroscience↗

bioRxiv2023

A direct estrogenic involvement in the expression of human hypocretin

BackgroundHypocretin-1 may play an important role in depression, which was increased in female depression in LHA in our previous study. Estrogen acts through its nuclear transcriptional receptors. MethodsWe studied the possibility of a direct action of estrogen receptors on the expression of human hypocretin. To explore the activation of ERs by hypocretin, we first investigated the potential presence of co-localization of the estrogen receptors (ERs) in hypocretin-immunoreactive neurons in the lateral hypothalamic area (LHA) in human and nuclear ERs in hypocretin immunoreactive neuroblastoma SK-N-SH cells. We investigated the relationship between E2 and hypocretin in female rats. After we explored the regulating role of exogenous estrogen on hypocretin gene expression via ERs through Chromatin immunoprecipitation, Electrophoretic mobility shift assay and Luciferase assay. ResultsWe found that hypocretin-1 plasma level was significantly higher in female depression. Estrogen receptors (ER and ER{beta}) and hypocretin are co-localized in female depression LHA, PC12 and SK-N-SH cell lines. The estrogen receptor response elements (EREs) existing in the hypocretin promoter region may directly regulate the expression of hypocretin, the synchronicity of change of hypocretin and estradiol both in hypothalamus and plasma was verified in female rats. With the presence of estradiol, there is specific binding between human ER and the Hypocretin-ERE. Expression of ER combined with estradiol repressed hypocretin promoter activity through the ERE. Conclusionswe defined that estradiol may affect hypocretin neurons in the human hypothalamus via ER binding to the Hypocretin-ERE directly, which may thus lead to the sex-specific pathogenesis of depression.

neuroscience↗

bioRxiv2023

Age-Related Changes of Dopamine D1 and D2 Receptors Expression in Parvalbumin-Positive Cells of the Orbitofrontal and Prelimbic Cortices of Mice

Dopamine (DA) plays a pivotal role in reward processing, cognitive functions, and emotional regulation. The prefrontal cortex (PFC) is a critical brain region for these processes. Parvalbumin-positive (PV+) neurons are one of the major classes of inhibitory GABAergic neurons in the cortex, they modulate the activity of neighboring neurons, influencing various brain functions. While DA receptor expression exhibits age-related changes, the age-related changes of these receptors in PV+ neurons, especially in the PFC, remains unclear. To address this, we investigated the expression of DA D1 (D1R) and D2 (D2R) receptors in PV+ neurons within the orbitofrontal (OFC) and prelimbic (PrL) cortices at different postnatal ages (P28, P42, P56, and P365). We found that the expression of D1R and D2R in PV+ neurons showed both age- and region-related changes. PV+ neurons in the OFC expressed a higher abundance of D1 than those in the PrL, and those neurons in the OFC also showed higher co-expression of D1R and D2R than those in the PrL. In both the OFC and PrL, D1R in PV+ neurons increased from P28 and reached a plateau at P42, then receded to express at P365. Meanwhile, D2R did not show significant age-related changes in both regions. These results showed dopamine receptors in the prefrontal cortex exhibit age- and region-specific changes, which may contribute to the difference of these brain regions in reward-related brain functions.

neuroscience↗

bioRxiv2023

uniLIVER: a Human Liver Cell Atlas for Data-Driven Cellular State Mapping

The liver performs several vital functions such as metabolism, toxin removal and glucose storage through the coordination of various cell types. The cell type compositions and cellular states undergo significant changes in abnormal conditions such as fatty liver, cirrhosis and liver cancer. As the recent breakthrough of the single-cell/single-nucleus RNA-seq (sc/snRNA-seq) techniques, there is a great opportunity to establish a reference cell map of liver at single cell resolution with transcriptome-wise features. In this study, we build a unified liver cell atlas uniLIVER by integrative analyzing a large-scale sc/snRNA-seq data collection of normal human liver with 331,125 cells and 79 samples from 6 datasets. Besides the hierarchical cell type annotations, uniLIVER also proposed a novel data-driven strategy to map any query dataset to the normal reference map by developing a machine learning based framework named LiverCT. Applying LiverCT on the datasets from multiple abnormal conditions (1,867,641 cells and 439 samples from 12 datasets), the alterations of cell type compositions and cellular states were systematically investigated in liver cancer.

bioinformatics↗