Biology subjects

Han, C.

Publications and source records attributed to Han, C..

At least 109 records · Page 6Linked to original sources

bioRxiv2021

Limited variation between SARS-CoV-2-infected individuals in domain specificity and relative potency of the antibody response against the spike glycoprotein

The spike protein of SARS-CoV-2 is arranged as a trimer on the virus surface, composed of three S1 and three S2 subunits. Infected and vaccinated individuals generate antibodies against spike, which can neutralize the virus. Most antibodies target the receptor-binding domain (RBD) and N-terminal domain (NTD) of S1; however, antibodies against other regions of spike have also been isolated. The variation between infected individuals in domain specificity of the antibodies and in their relative neutralization efficacy is still poorly characterized. To this end, we tested serum and plasma samples from 85 COVID-19 convalescent subjects using 7 immunoassays that employ different domains, subunits and oligomeric forms of spike to capture the antibodies. Samples were also tested for their neutralization of pseudovirus containing SARS-CoV-2 spike and of replication-competent SARS-CoV-2. We observed strong correlations between the levels of NTD- and RBD-specific antibodies, with a fixed ratio of each type to all anti-spike antibodies. The relative potency of the response (defined as the measured neutralization efficacy relative to the total level of spike-targeting antibodies) also exhibited limited variation between subjects, and was not associated with the overall amount of anti-spike antibodies produced. Accordingly, the ability of immunoassays that use RBD, NTD and different forms of S1 or S1/S2 as capture antigens to estimate the neutralizing efficacy of convalescent samples was largely similar. These studies suggest that host-to-host variation in the polyclonal response elicited against SARS-CoV-2 spike is primarily limited to the quantity of antibodies generated rather than their domain specificity or relative neutralization potency. IMPORTANCEInfection by SARS-CoV-2 elicits antibodies against various domains of the spike protein, including the RBD, NTD and S2. Different infected individuals generate vastly different amounts of anti-spike antibodies. By contrast, as we show here, there is a remarkable similarity in the properties of the antibodies produced. Different individuals generate the same proportions of antibodies against each domain of the spike protein. Furthermore, the relationship between the amount of anti-spike antibodies produced and their neutralization efficacy of SARS-CoV-2 is highly conserved. Therefore, the observed variation in the neutralizing activity of the antibody response in COVID-19 convalescent subjects is caused by differences in the amounts of antibodies rather than their recognition properties or relative antiviral activity. These findings suggest that COVID-19 vaccine strategies that focus on enhancing the overall level of the antibodies will likely elicit a more uniformly efficacious protective response.

microbiology↗

bioRxiv2021

MicroRNA-202 prevents precocious spermatogonial differentiation and meiotic initiation during mouse spermatogenesis

Spermatogonial differentiation and meiotic initiation during spermatogenesis are tightly regulated by a number of genes including those coding enzymes for miRNA biogenesis. However, whether and how single miRNAs regulate these processes remain unclear. Here, we report that miR-202, a member of the let-7 family, prevents precocious spermatogonial differentiation and meiotic initiation in spermatogenesis by regulating the timely expression of many genes including those for other key regulators. In miR-202 knockout (KO) mice, the undifferentiated spermatogonial pool is reduced, ultimately causing agametic seminiferous tubules. SYCP3, STRA8 and DMRT6 are expressed earlier in KO mice than in wild-type (WT) littermates, and Dmrt6 mRNA is a direct target of miR-202-5p. Moreover, the precocious spermatogonial differentiation and meiotic initiation were also observed in KO spermatogonial stem cells when cultured and induced in vitro, and could be rescued by the knockdown of Dmrt6. Therefore, we have not only shown that miR-202 is a novel regulator of meiotic initiation but also added a new module to the underlying regulatory network. Summary statementA single miRNA, miR-202, prevents precocious differentiation and meiotic initiation during spermatogenesis. miR-202, DMRT6 and STRA8 act together as a novel module in the regulatory network of meiotic initiation.

developmental biology↗

bioRxiv2021

Combining Multi-Dimensional Molecular Fingerprints to Predict hERG Cardiotoxicity of Compounds

At present, drug toxicity has become a critical problem with heavy medical and economic burdens. acLQTS (acquired Long QT Syndrome) is acquired cardiac ion channel disease caused by drugs blocking the hERG channel. Therefore, it is necessary to avoid cardiotoxicity in the drug design and computer models have been widely used to fix this plight. In this study, we present a molecular fingerprint based on the molecular dynamic simulation and uses it combined with other molecular fingerprints (multi-dimensional molecular fingerprints) to predict hERG cardiotoxicity of compounds. 203 compounds with hERG inhibitory activity (pIC50) were retrieved from a previous study and predicting models were established using four machine learning algorithms based on the single and multi-dimensional molecular fingerprints. Results showed that MDFP has the potential to be an alternative to traditional molecular fingerprints and the combination of MDFP and traditional molecular fingerprints can achieve higher prediction accuracy. Meanwhile, the accuracy of the best model, which was generated by consensus of four algorithms with multi-dimensional molecular fingerprints, was 0.694 (RMSE) in the test dataset. Besides, the number of hydrogen bonds from MDFP has been determined as a critical factor in the predicting models, followed by rgyr and sasa. Our findings provide a new sight of MDFP and multi-dimensional molecular fingerprints in building models of hERG cardiotoxicity prediction.

pharmacology and toxicology↗

bioRxiv2021

Gene regulatory networks underlying human microglia maturation

The fetal period is a critical time for brain development, characterized by neurogenesis, neural migration, and synaptogenesis1-3. Microglia, the tissue resident macrophages of the brain, are observed as early as the fourth week of gestation4 and are thought to engage in a variety of processes essential for brain development and homeostasis5-11. Conversely, microglia phenotypes are highly regulated by the brain environment12-14. Mechanisms by which human brain development influences the maturation of microglia and microglia potential contribution to neurodevelopmental disorders remain poorly understood. Here, we performed transcriptomic analysis of human fetal and postnatal microglia and corresponding cortical tissue to define age-specific brain environmental factors that may drive microglia phenotypes. Comparative analysis of open chromatin profiles using bulk and single-cell methods in conjunction with a new computational approach that integrates epigenomic and single-cell RNA-seq data allowed decoding of cellular heterogeneity with inference of subtype- and development stage-specific transcriptional regulators. Interrogation of in vivo and in vitro iPSC-derived microglia models provides evidence for roles of putative instructive signals and downstream gene regulatory networks which establish human-specific fetal and postnatal microglia gene expression programs and potentially contribute to neurodevelopmental disorders.

genomics↗

bioRxiv2021

MicroRNA-202 safeguards meiotic progression by preventing premature degradation of REC8 mediated by separase

MicroRNAs (miRNAs) are believed to play important roles in mammalian spermatogenesis but the in vivo functions of single miRNAs in this highly complex developmental process remain unclear. Here, we reported that miR-202, a member of the let-7 family, played an important role in mouse spermatogenesis by phenotypic evaluation of miR-202 knockout (KO) mice. In miR-202 KO mice, germ cells underwent apoptosis. Multiple processes in meiosis I including synapsis and crossover formation were disrupted, and inter-sister chromatid synapses were detected. More importantly, we found that upon miR-202 KO, meiotic-specific cohesin protein REC8 was prematurely cleaved by precociously activated separase, whose mRNA was a direct target of miR-202-3p. Our findings identify miR-202 as a novel regulator of meiosis and contribute to the list of miRNAs that play specific and important roles in developmental processes.

developmental biology↗

bioRxiv2020

Controlling Cellular Arrangements via Stretched Bioprinting

Bioprinting is a common method to replicate geometrical architecture of native tissues. However, it usually fails to modulate cellular arrangements, which is critical for the tissues functionality. To our knowledge, no method has successfully addressed this challenge. Here, we report a method of controlling cellular orientation during the bioprinting process by integrating a stretch process into a modified bioprinting frame. We demonstrate that the cellular orientation is a result of cells sensing and responding to the tensile stress, instead of shear stress or topographical patterns. Moreover, our method shows a potent capability to induce myoblast differentiation, fusion and maturation without the presence of differentiation medium. As a potential clinical application, we demonstrate that aligned myofibers directly printed onto injured muscle in vivo, can not only repair the structure of damaged tissue, but also recover the muscle functionalities effectively. This study shows that the new method can produce tissues with precise control of cellular arrangements and more clinically viable functionalities. Significance StatementDue to no method could reproduce the exact cellular arrangements of native tissues in engineered tissues, tissue engineering facing difficult in fabricating 3D tissues that possess desirable biological and mechanical functionalities for biomedical applications. For the first time, we report a method of controlling cellular orientation during 3D bio-printing process. This method can be used to produce engineered tissues with controlled cellular arrangement with several different cell types. Moreover, this method shows a potent capability of fabricating fully mature and aligned myofibers in vitro in the absence of differentiation medium. As potential clinical applications, with this method, engineered tissues could be directly printed in vivo with high efficacy of tissue repair and function recovery.

cell biology↗

bioRxiv2020

The fusion peptide proximal region of the HIV-1 envelope glycoproteins regulates exposure of immunogenic epitopes at the trimer base

The error-prone replication machinery of HIV-1 continuously generates new variants of the envelope glycoproteins (Envs). Antibody selection pressures applied in the host can limit their persistence. The target specificity of antibodies elicited in different hosts varies considerably. Whether some specificities are shared and have affected the population-level evolution of Env structure is still unclear. We examined the historical changes in amino acid sequence of the gp41 fusion peptide proximal region (FPPR), which is not exposed on the Env trimer. For three FPPR positions, the residue found in the clade B ancestor was mainly replaced by alanine. However, the changes in alanine frequency at these positions between 1979 and 2016 followed different patterns; two positions maintained a historically-constant frequency whereas the third showed a gradual increase. To understand these patterns, we introduced alanine substitutions in the FPPR of primary HIV-1 strains and examined their fitness and antigenicity relative to the clade-ancestral form. The evolutionary patterns could not be explained by effects on Env fitness. Instead, the FPPR variants with a historically-constant alanine frequency exhibited a unique open-at-the-base conformation of the trimer that exposes partially-cryptic epitopes. These Envs were modestly but significantly more sensitive to poorly-neutralizing sera from HIV-infected individuals than the clade-ancestral form. Our findings suggest that weakly-neutralizing antibodies targeting the base of the trimer are commonly elicited. Such low-level antibody pressures do not exert catastrophic effects on the emerging variants but rather determine their set-point frequency in the population and historical patterns of change. IMPORTANCEHIV-1 infection elicits antibodies that target the Env proteins of the virus. The specific targets of these antibodies vary between infected individuals. It is unclear whether some target specificities are shared between the antibody responses of different individuals. Our data suggest that antibodies against the base of the Env protein are commonly elicited during infection and are contained in sera with low neutralization efficacy. Such antibody pressures are weak. As a result, they do not completely eliminate the sensitive Env forms from the population, but rather maintain their frequency at a low level that has not increased during the past 40 years.

microbiology↗

bioRxiv2020

A novel family of secreted proteins linked to plant gall development

In an elaborate form of inter-species exploitation, many insects hijack plant development to induce novel plant organs called galls that provide the insect with a source of nutrition and a temporary home. Galls result from dramatic reprogramming of plant cell biology driven by insect molecules, but the roles of specific insect molecules in gall development have not yet been determined. Here we study the aphid Hormaphis cornu, which makes distinctive "cone" galls on leaves of witch hazel Hamamelis virginiana. We found that derived genetic variants in the aphid gene determinant of gall color (dgc) are associated with strong downregulation of dgc transcription in aphid salivary glands, upregulation in galls of seven genes involved in anthocyanin synthesis, and deposition of two red anthocyanins in galls. We hypothesize that aphids inject DGC protein into galls, and that this results in differential expression of a small number of plant genes. Dgc is a member of a large, diverse family of novel predicted secreted proteins characterized by a pair of widely spaced cysteine-tyrosine-cysteine (CYC) residues, which we named BICYCLE proteins. Bicycle genes are most strongly expressed in the salivary glands specifically of galling aphid generations, suggesting that they may regulate many aspects of gall development. Bicycle genes have experienced unusually frequent diversifying selection, consistent with their potential role controlling gall development in a molecular arms race between aphids and their host plants. One Sentence SummaryAphid bicycle genes, which encode diverse secreted proteins, contribute to plant gall development.

genetics↗

bioRxiv2020

Diet unmasks genetic variants that regulate lifespan in outbred Drosophila

Evolutionary theory suggests that lifespan-associated alleles should be purged from the gene pool, and yet decades of GWAS and model organism studies have shown they persist. Here, we address one potential explanation, the idea that the alleles that regulate lifespan do so only in certain contexts. We exposed thousands of outbred Drosophila to a standard and a high sugar diet. We then sequenced over 10,000 individuals and track genome-wide allele frequency changes over time, as these populations aged. We mapped thousands of lifespan-altering alleles, some associated with early vs late life tradeoffs, late-onset effects, and genotype-by-environment interactions. We find that lifespan-reducing alleles are most likely to be recently derived, have stronger effects on a high-sugar diet, consistent with the hypothesis that historically neutral or beneficial alleles can become detrimental in novel conditions. We also show that the gene midway, a regulator of lipid storage and ortholog of the lifespan-associated gene DGAT1 in mice, also regulates lifespan in Drosophila. Our results provide insight into the highly polygenic and context-dependent genetic architecture of lifespan, as well as the evolutionary processes that shape this key trait.

evolutionary biology↗

bioRxiv2020

Inhibiting DDX3X triggers tumor-intrinsic type I interferon response and enhances anti-tumor immunity

Accumulating evidence has shown that cellular double-stranded RNAs (dsRNAs) induce antiviral innate immune responses in human normal and malignant cancer cells. However, it is not fully understood how endogenous self dsRNA homeostasis is regulated in the cell. Here, we show that an RNA-binding protein, DEAD-box RNA helicase 3X (DDX3X), prevents the aberrant accumulation of cellular dsRNAs. Loss of DDX3X induces dsRNA sensor-mediated type I interferon signaling and innate immune response in breast cancer cells due to abnormal cytoplasmic accumulation of dsRNAs. Dual depletion of DDX3X and a dsRNA-editing protein, ADAR1 synergistically activates the cytosolic dsRNA pathway in breast cancer cell. Moreover, inhibiting DDX3X enhances the antitumor activity by increasing tumor intrinsic-type I interferon response, antigen presentation, and tumor-infiltration of cytotoxic T cells as well as dendritic cells in breast tumors, which may lead to the development of breast cancer therapy by targeting DDX3X in combination with immune checkpoint blockade.

cancer biology↗

bioRxiv2020

Genome-wide association study of TP53 R249S mutation in hepatocellular carcinoma with aflatoxin B1 exposure and hepatitis B virus infection in Guangxi

Background/AimsDietary aflatoxin B1 (AFB1) exposure, which induces DNA damage and codon 249 mutation of the TP53 gene, is one of the major risk factors for hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) infection and AFB1 exert synergistic effects to promote carcinogenesis and TP53 R249S mutation in HCC. MethodsA genome-wide association study (GWAS) was conducted on 485 cases of HCC with chronic HBV infection, followed by a two-stage replication study on 270 cases with chronic HBV infection. Susceptibility variants for the TP53 R249S mutation in HCC were identified based on both GWAS and replication analysis. The associations of identified variants with expression levels of their located genes were validated in 20 paired independent samples. ResultsOur results showed that TP53 R249S was significantly associated with ADAMTS18 rs9930984 (adjusted P = 4.84x10-6), WDR49 rs75218075 (adjusted P = 7.36 x 10-5) and SLC8A3 rs8022091 (adjusted P = 0.042). Additionally, ADAMTS18 mRNA expression was significantly higher in HCC tissue, compared with paired non-tumor tissue (P = 0.041) and patients carrying the TT genotype at rs9930984 showed lower ADAMTS18 expression in non-tumor tissue, compared with those carrying the GT genotype (P = 0.0028). ConclusionsTP53 expression is significantly associated with R249S mutation in HCC. Our collective results suggest that rs9930984, rs75218075 and rs8022091 are associated with susceptibility to the R249S mutation in cases of HCC exposed to AFB1 and HBV infection.

genetics↗

bioRxiv2020

Early defects in lysosomal storage diseases disrupt excitatory synaptic transmission

At least two thirds of patients affected with lysosomal storage disorders (LSD) exhibit neurological symptoms. For mucopolysaccharidosis type IIIC (MPS IIIC, Sanfilippo disease type C) caused by mutations in the HGSNAT gene and lysosomal storage of heparan sulfate the major burden is progressive and severe neuropsychiatric problems, mental retardation, and dementia though to be mainly mediated by neurodegeneration. HGSNAT knockout mice match human clinical phenotype and develop hyperactivity followed by memory impairment and death. In order to understand whether early clinical symptoms in MPS IIIC mice occurring before the onset of massive neurodegeneration are caused by neuronal dysfunction we studied synaptic transmission and morphology in cultured hippocampal and CA1 pyramidal neurons of MPSIIIC mice. Synaptic spines were also studied in other mouse LSD models and postsynaptic densities in post-mortem cortices of human neurological MPS patients. Cultured hippocampal and CA1 pyramidal neurons of MPS IIIC mice showed a drastic decrease or abnormal distribution of multiple pre- and postsynaptic proteins that could be rescued in vitro and in vivo by virus-mediated gene correction. Dendritic spine densities were immature in cultured hippocampal MPS IIIC mouse neurons and reduced in pyramidal neurons of mouse models of MPS IIIC and other (Tay-Sachs, sialidosis) LSD starting from postnatal day 10. MPS IIIC neurons presented alterations in frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents, sparse synaptic vesicles, reduced postsynaptic densities, disorganised microtubule network and partially impaired axonal transport of synaptic proteins. Postsynaptic densities were also reduced in post-mortem cotrees of human MPS I, II, IIIA, C and D patients suggesting that the pathology is common for these neurological LSD. Together, our results demonstrate that lysosomal storage causes alterations in synaptic structure and abnormalities in neurotransmission originating from disrupted vesicular transport and preceding the first cognitive symptoms and suggest drugs known to affect synaptic transmission can be potentially applied to treat behavioral and cognitive defects in neurological LSD patients.

neuroscience↗

bioRxiv2020

Upgraded CRISPR/Cas9 Tools for Tissue-Specific Mutagenesis in Drosophila

ABSTRACTCRISPR/Cas9 has emerged as a powerful technology for tissue-specific mutagenesis. However, tissue-specific CRISPR/Cas9 tools currently available in Drosophila remain deficient in three significant ways. First, many existing gRNAs are inefficient, such that further improvements of gRNA expression constructs are needed for more efficient and predictable mutagenesis in both somatic and germline tissues. Second, it has been difficult to label mutant cells in target tissues with current methods. Lastly, application of tissue-specific mutagenesis at present often relies on Gal4-driven Cas9, which hampers the flexibility and effectiveness of the system. Here we tackle these deficiencies by building upon our previous CRISPR-mediated tissue restricted mutagenesis (CRISPR-TRiM) tools. First, we significantly improved gRNA efficiency in somatic tissues by optimizing multiplexed gRNA design. Similarly, we also designed efficient dual-gRNA vectors for the germline. Second, we developed methods to positively and negatively label mutant cells in tissue-specific mutagenesis by incorporating co-CRISPR reporters into gRNA expression vectors. Lastly, we generated genetic reagents for convenient conversion of existing Gal4 drivers into tissue-specific Cas9 lines based on homology-assisted CRISPR knock-in (HACK). In this way, we expand the choices of Cas9 for CRISPR-TRiM analysis to broader tissues and developmental stages. Overall, our upgraded CRISPR/Cas9 tools make tissue-specific mutagenesis more versatile, reliable, and effective in Drosophila. These improvements may be also applied to other model systems.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2020

MAGIC: Mosaic Analysis by gRNA-Induced Crossing-over

Mosaic animals have provided the platform for many fundamental discoveries in developmental biology, cell biology, and other fields. Techniques to produce mosaic animals by mitotic recombination have been extensively developed in Drosophila melanogaster but are less common for other laboratory organisms. Here, we report mosaic analysis by gRNA-induced crossing-over (MAGIC), a new technique for generating mosaic animals based on DNA double-strand breaks produced by CRISPR/Cas9. MAGIC efficiently produces mosaic clones in both somatic tissues and the germline of Drosophila. Further, by developing a MAGIC toolkit for one chromosome arm, we demonstrate the method’s application in characterizing gene function in neural development and in generating fluorescently marked clones in wild-derived Drosophila strains. Eliminating the need to introduce recombinase-recognition sites in the genome, this simple and versatile system simplifies mosaic analysis in Drosophila and can be applied in any organism that is compatible with CRISPR/Cas9.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genetics↗

bioRxiv2020

Phagocytosis drives NAD+ reduction-induced dendrite degeneration in Drosophila

After injury, severed dendrites and axons expose the "eat-me" signal phosphatidylserine (PS) on their surface and degenerate by disassembly. While axon degeneration is controlled by a conserved "axon-death" pathway that is thought to activate self-destruction, how PS exposure is regulated by this pathway and whether PS-induced phagocytosis contributes to neurite breakdown in vivo remain unknown. Here we show that in Drosophila sensory dendrites, PS exposure and self-destruction are triggered by two distinct levels of NAD+ reduction downstream of Sarm activation. Surprisingly, phagocytosis is the main driver of dendrite degeneration induced by both genetic NAD+ disruptions and injury. Furthermore, the axon-death factor Axed is only partially required for self-destruction of injured dendrites, acting in parallel with PS-induced phagocytosis. Lastly, injured dendrites exhibit a unique rhythmic calcium flashing that correlates with self-destruction. Therefore, a special genetic program coordinates PS exposure and self-destruction in injury-induced dendrite degeneration in vivo.

cell biology↗

bioRxiv2020

Genome-wide identification of long non-coding RNAs in the gravid ectoparasite Varroa destructor

Long non-coding RNAs (lncRNAs) emerge as critical regulators with various biological functions in living organisms. However, to date, no systematic characterization of lncRNAs has been investigated in the ectoparasitic mite Varroa destructor, the most severe biotic threat to honey bees worldwide. Here, we performed an initial genome-wide identification of lncRNAs in V. destructor via high-throughput sequencing technology and reported, for the first time, the transcriptomic landscape of lncRNAs in the devastating parasite. By means of a lncRNA identification pipeline, 6,645 novel lncRNA transcripts, encoded by 3,897 gene loci, were identified, including 2,066 sense lncRNAs, 2,772 lincRNAs, and 1,807 lncNATs. Compared with protein-coding mRNAs, V. destructor lncRNAs are shorter in terms of full length, as well as of the ORF length, contain less exons, and express at lower level. GO term and KEGG pathway enrichment analyses of the lncRNA target genes demonstrated that these predicted lncRNAs are likely to play key roles in cellular processes, genetic information processing and environmental responses. To our knowledge, this is the first catalog of lncRNA profile in the parasitiformes species, providing a valuable resource for genetic and genomic studies. Understanding the characteristics and features of lncRNAs in V. destructor would promote sustainable pest control.

genomics↗

bioRxiv2020

Ultra-sensitive nanozyme-based chemiluminescence paper test for rapid diagnosis of SARS-CoV-2 infection

The recently emerged coronavirus disease COVID-19 has now evolved into a global pandemic. Early detection is crucial for its effective control. Nucleic acid testing for viral pathogen and serological testing for host antibodies are playing important roles in current COVID-19 diagnosis. However, while nucleic acid testing is complicated, facility-restricted and time-consuming, antibody testing may result in high rates of false-negative diagnoses, especially during the early stages of viral infection. Thus, a more rapid and reliable test for both early COVID-19 diagnosis and whole-population screening is urgently needed. Here, we developed a novel nanozyme-based chemiluminescence paper assay for rapid and high-sensitive testing of SARS-CoV-2 spike antigen. Our paper test uses a newly established peroxidase-mimic Co-Fe@hemin nanozyme instead of natural HRP that catalytically amplifies the chemiluminescent signal, allowing for target concentrations to be as low as 0.1 ng/ml. Furthermore, our nanozyme-based chemiluminescence test exhibits a linear range that is 32-fold wider compared to ELISA tests. Importantly, testing is completed in less than 16 min, compared to 1-2 h required for ELISA or nucleic acid tests. Critically, signal detection is feasible using a smartphone camera. Ingredients for our test are simple and readily available, rendering overall cost considerably lower than those used in current diagnoses. In conclusion, our novel test provides a high-sensitive, point-of-care testing (POCT) approach for SARS-CoV-2 antigen detection, which should greatly increase current early screening capacities for suspected infections, and considerably lower demand for national healthcare resources.

microbiology↗

bioRxiv2020

Predicting cell fate commitment of embryonic differentiation by single-cell graph entropy

Cell fate commitment occurs during early embryonic development, that is, the embryonic differentiation sometimes undergoes a critical phase transition or "tipping point" of cell fate commitment, at which there is a drastic or qualitative shift of the cell populations. In this study, we presented a novel computational approach, the single-cell graph entropy (SGE), to explore the gene-gene associations among cell populations based on single-cell RNA sequencing (scRNA-seq) data. Specifically, by transforming the sparse and fluctuating gene expression data to the stable local network entropy, the SGE score quantitatively characterizes the criticality of gene regulatory networks among cell populations, and thus can be employed to predict the tipping point of cell fate or lineage commitment at the single cell level. The proposed SGE method was applied to five scRNA-seq datasets. For all these datasets of embryonic differentiation, SGE effectively captures the signal of the impending cell fate transitions, which cannot be detected by gene expressions. Some "dark" genes that are non-differential but sensitive to SGE values were revealed. The successful identification of critical transition for all five datasets demonstrates the effectiveness of our method in analyzing scRNA-seq data from a network perspective, and the potential of SGE to track the dynamics of cell differentiation.

bioinformatics↗