Biology subjects

Liang, C.

Publications and source records attributed to Liang, C..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Live-cell single-molecule dynamics of eukaryotic RNA polymerase machineries

Eukaryotic gene expression in the nucleus is orchestrated by three RNA polymerases (RNAP-I, -II, and -III) and associated factors1,2. Despite extensive biochemical, genomic, structural, and imaging studies, the real-time dynamics of these transcription complexes remain obscure. Here, we employ single-molecule tracking in living yeast to assess the physiological kinetics of over 50 representative proteins encompassing all three RNAP machineries. Components of RNAPI and RNAPIII pre-initiation complexes (PICs) engage in long-lived interactions on chromatin, reflecting their roles for constitutive rRNA and tRNA synthesis, in contrast to the transient RNAPII PIC. We further report the dynamics of key components across the RNAPII transcription cycle2-5--factors for upstream regulation, elongation, histone modification, RNAPII C-terminal domain (CTD) modification, RNA processing, and termination--revealing unprecedented insights into the temporal landscape of RNAPII transcription. Strikingly, many elongation factors, previously thought to travel processively with RNAPII, display transient residence times, suggesting highly dynamic interactions rather than constant association. Systematic screening of RNAPII-associated factors shows that truncation of RNAPII-CTD substantially reduces U1 snRNP residence time and decreases intron retention in ribosomal protein genes, providing insights into how CTD length influences co-transcriptional splicing. Our findings establish a framework for dynamic chromatin interactions of RNA polymerase machineries in living cells.

biophysics↗

bioRxiv2024

An Artificial Intelligence Model for Profiling the Landscape of Antigen-binding Affinities of Massive BCR Sequencing Data

The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in cancers and other biological contexts. The capability to profile the landscape of antigen-binding affinities of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for detecting antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of binding between antibodies and antigens that can be scaled to high-throughput sequencing data. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data to predict the landscape of the antigen-binding affinities of the BCRs. We found that extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of immune-checkpoint inhibitor (ICI) treatment response. On the other hand, we found that, during immune-related adverse events (irAEs) caused by ICI treatment, humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. Overall, we developed a powerful tool for elucidating the antigen binding landscape of BCR repertoires, and it shall also propell antibody-centric translational applications for cancers and other diseases.

immunology↗

bioRxiv2024

iLipidome: enhancing statistical power and interpretability using hidden biosynthetic interdependencies in the lipidome

Numerous biological processes and diseases are influenced by lipid composition. Advances in lipidomics are elucidating their roles, but analyzing and interpreting lipidomics data at the systems level remain challenging. To address this, we present iLipidome, a method for analyzing lipidomics data in the context of the lipid biosynthetic network, thus accounting for the interdependence of measured lipids. iLipidome enhances statistical power, enables reliable clustering and lipid enrichment analysis, and links lipidomic changes to their genetic origins. We applied iLipidome to investigate mechanisms driving changes in cellular lipidomes following supplementation of docosahexaenoic acid (DHA) and successfully identified the genetic causes of alterations. We further demonstrated how iLipidome can disclose enzyme-substrate specificity and pinpoint prospective glioblastoma therapeutic targets. Finally, iLipidome enabled us to explore underlying mechanisms of cardiovascular disease and could guide the discovery of early lipid biomarkers. Thus, iLipidome can assist researchers studying the essence of lipidomic data and advance the field of lipid biology.

systems biology↗

bioRxiv2024

Flp-recombinase mouse line for genetic manipulation of ipRGCs

Light has myriad impacts on behavior, health, and physiology. These signals originate in the retina and are relayed to the brain by more than 40 types of retinal ganglion cells (RGCs). Despite a growing appreciation for the diversity of RGCs, how these diverse channels of light information are ultimately integrated by the [~]50 retinorecipient brain targets to drive these light-evoked effects is a major open question. This gap in understanding primarily stems from a lack of genetic tools that specifically label, manipulate, or ablate specific RGC types. Here, we report the generation and characterization of a new mouse line (Opn4FlpO), in which FlpO is expressed from the Opn4 locus, to manipulate the melanopsin-expressing, intrinsically photosensitive retinal ganglion cells. We find that the Opn4FlpO line, when crossed to multiple reporters, drives expression that is confined to ipRGCs and primarily labels the M1-M3 subtypes. Labeled cells in this mouse line show the expected intrinsic, melanopsin-based light response and morphological features consistent with the M1-M3 subtypes. In alignment with the morphological and physiological findings, we see strong innervation of non-image forming brain targets by ipRGC axons, and weaker innervation of image forming targets in Opn4FlpO mice labeled using AAV-based and FlpO-reporter lines. Consistent with the FlpO insertion disrupting the endogenous Opn4 transcript, we find that Opn4FlpO/FlpO mice show deficits in the pupillary light reflex, demonstrating their utility for behavioral research in future experiments. Overall, the Opn4FlpO mouse line drives Flp-recombinase expression that is confined to ipRGCs and most effectively drives recombination in M1-M3 ipRGCs. This mouse line will be of broad use to those interested in manipulating ipRGCs through a Flp-based recombinase for intersectional studies or in combination with other, non-Opn4 Cre driver lines.

neuroscience↗

bioRxiv2024

Ontology-based modeling, integration, and analysis of heterogeneous clinical, pathological, and molecular kidney data for precision medicine

Many resources are now generating, processing, storing, or providing kidney-related molecular, pathological, and clinical data. Reference ontologies offer an opportunity to support knowledge and data organization and integration. The Kidney Precision Medicine Project (KPMP) team contributed to the representation and addition of 329 kidney phenotype terms to the Human Phenotype Ontology (HPO) and identified many subcategories of acute kidney injury (AKI) or chronic kidney disease (CKD). The Kidney Tissue Atlas Ontology (KTAO) imports and integrates kidney-related terms from existing ontologies (e.g., HPO, CL, and Uberon) and represents 259 kidney-related biomarkers. We also developed a precision medicine metadata ontology (PMMO) to integrate 50 variables from KPMP and CellxGene resources and applied PMMO for integrative analysis. The gene expression profiles of kidney gene biomarkers were specifically analyzed in healthy controls or AKI/CKD disease states. This work demonstrates how ontology-based approaches support multi-domain data and knowledge organization and integration to advance precision medicine.

bioinformatics↗

bioRxiv2024

UBA1-CDK16: A Sex-Specific Chimeric RNA and Its Role in Immune Sexual Dimorphism

RNA processing mechanisms, such as alternative splicing and RNA editing, have been recognized as critical means to expand the transcriptome. Chimeric RNAs formed by intergenic splicing provide another potential layer of RNA diversification. By analyzing a large set of RNA-Seq data and validating results in over 1,200 blood samples, we identified UBA1-CDK16, a female-specific chimeric transcript. Intriguingly, both parental genes, are expressed in males and females. Mechanistically, UBA1-CDK16 is produced by cis-splicing between the two adjacent X-linked genes, originating from the inactive X chromosome. A female-specific chromatin loop, formed between the junction sites, facilitates the alternative splicing of its readthrough precursor. This unique chimeric transcript exhibits evolutionary conservation, evolving to be female-specific from non-human primates to humans. Furthermore, our investigation reveals that UBA1-CDK16 is enriched in the myeloid lineage and plays a regulatory role in myeloid differentiation. Notably, female COVID-19 patients who tested negative for this chimeric transcript displayed higher counts of neutrophils, highlighting its potential role in disease pathogenesis. These findings support the notion that chimeric RNAs represent a new repertoire of transcripts that can be regulated independently from the parental genes, and a new class of RNA variance with potential implications in sexual dimorphism and immune responses.

genomics↗

bioRxiv2024

miR-26 deficiency causes alterations in lens transcriptome and results in adult-onset cataract

PurposeDespite strong evidence demonstrating that normal lens development requires regulation governed by miRNAs, the functional role of specific miRNAs in mammalian lens development remains largely unexplored. MethodsA comprehensive analysis of miRNA transcripts in the newborn mouse lens, exploring both differential expression between lens epithelial cells and lens fiber cells and overall miRNA abundance was conducted by miRNA-seq. Mouse lenses lacking each of three abundantly expressed lens miRNAs: miR-184, miR-26 and miR-1 were analyzed to explore the role of these miRNAs in lens development. ResultsMice lacking all three copies of miR-26 (miR-26TKO) developed postnatal cataracts as early as 4-6 weeks of age. RNA-seq analysis of neonatal lenses from miR-26TKO mice exhibited abnormal reduced expression of a cohort of genes found to be lens-enriched and linked to cataract (e.g. Foxe3, Hsf4, Mip, Tdrd7, and numerous crystallin genes), and abnormal elevated expression of genes related to neural development (Lhx3, Neurod4, Shisa7, Elavl3), inflammation (Ccr1, Tnfrsf12a, Csf2ra), the complement pathway, and epithelial to mesenchymal transition (Tnfrsf1a, Ccl7, Stat3, Cntfr). ConclusionmiR-1, miR-184 and miR-26 are each dispensable for normal embryonic lens development. However, loss of miR-26 causes lens transcriptome changes and drives cataract formation.

developmental biology↗

bioRxiv2023

pan-MHC and cross-Species Prediction of T Cell Receptor-Antigen Binding

Profiling the binding of T cell receptors (TCRs) of T cells to antigenic peptides presented by MHC proteins is one of the most important unsolved problems in modern immunology. Experimental methods to probe TCR-antigen interactions are slow, labor-intensive, costly, and yield moderate throughput. To address this problem, we developed pMTnet-omni, an Artificial Intelligence (AI) system based on hybrid protein sequence and structure information, to predict the pairing of TCRs of {beta} T cells with peptide-MHC complexes (pMHCs). pMTnet-omni is capable of handling peptides presented by both class I and II pMHCs, and capable of handling both human and mouse TCR-pMHC pairs, through information sharing enabled this hybrid design. pMTnet-omni achieves a high overall Area Under the Curve of Receiver Operator Characteristics (AUROC) of 0.888, which surpasses competing tools by a large margin. We showed that pMTnet-omni can distinguish binding affinity of TCRs with similar sequences. Across a range of datasets from various biological contexts, pMTnet-omni characterized the longitudinal evolution and spatial heterogeneity of TCR-pMHC interactions and their functional impact. We successfully developed a biomarker based on pMTnet-omni for predicting immune-related adverse events of immune checkpoint inhibitor (ICI) treatment in a cohort of 57 ICI-treated patients. pMTnet-omni represents a major advance towards developing a clinically usable AI system for TCR-pMHC pairing prediction that can aid the design and implementation of TCR-based immunotherapeutics.

immunology↗

bioRxiv2023

Voluntary wheel running mitigates disease in an Orai1 gain-of-function mouse model of tubular aggregate myopathy

Tubular aggregate myopathy (TAM) is an inherited skeletal muscle disease associated with progressive muscle weakness, cramps, and myalgia. Tubular aggregates (TAs) are regular arrays of highly ordered and densely packed SR straight-tubes in muscle biopsies; the extensive presence of TAs represent a key histopathological hallmark of this disease in TAM patients. TAM is caused by gain-of-function mutations in proteins that coordinate store-operated Ca2+ entry (SOCE): STIM1 Ca2+ sensor proteins in the sarcoplasmic reticulum (SR) and Ca2+-permeable ORAI1 channels in the surface membrane. We have previously shown that voluntary wheel running (VWR) prevents formation of TAs in aging mice. Here, we assessed the therapeutic potential of endurance exercise (in the form of VWR) in mitigating the functional and structural alterations in a knock-in mouse model of TAM (Orai1G100S/+ or GS mice) based on a gain-of-function mutation in the ORAI1 pore. WT and GS mice were singly-housed for six months (from two to eight months of age) with either free-spinning or locked low profile wheels. Six months of VWR exercise significantly increased soleus peak tetanic specific force production, normalized FDB fiber Ca2+ store content, and markedly reduced TAs in EDL muscle from GS mice. Six months of VWR exercise normalized the expression of mitochondrial proteins found to be altered in soleus muscle of sedentary GS mice in conjunction with a signature of increased protein translation and biosynthetic processes. Parallel proteomic analyses of EDL muscles from sedentary WT and GS mice revealed changes in a tight network of pathways involved in formation of supramolecular complexes, which were also normalized following six months of VWR. In summary, sustained voluntary endurance exercise improved slow twitch muscle function, reduced the presence of TAs in fast twitch muscle, and normalized the muscle proteome of GS mice consistent with protective adaptions in proteostasis, mitochondrial structure/function, and formation of supramolecular complexes.

physiology↗

bioRxiv2023

Identification of an osteopontin-derived peptide that binds neuropilin-1 and activates vascular cells

BackgroundThe osteopontin-derived peptide FOL-005 has been shown to stimulate hair growth. Using ligand-receptor glycocapture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005. Considering that induction of perifollicular angiogenesis by VEGF is a critical step in activation of the anagen growth phase of hair follicles, we investigated the effect of the more stable FOL-005 analogue FOL-026 on vascular cells. MethodsX-ray diffraction and microscale thermophoresis analysis were used to determine receptor binding of FOL-peptides. Cultured human arterial smooth muscle cells were used for studies of cell proliferation, migration, intracellular signaling, and apoptosis. A Matrigel plug assay was used to study angiogenesis in vivo. RNA seq. was used to analyze changes in gene expression patterns. ResultsFOL-026 was found to share binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of AKT and ERK1/2, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro, as well as activation of angiogenesis in vivo. Down-regulation of NRP-1 by NRP-1-specific small interfering RNA blocked the stimulatory effects of FOL-026 on endothelial cells. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell proliferation, migration, inhibited apoptosis, and induced VEGF gene expression by an NRP-1-dependent mechanism. ConclusionsThese findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and / or enhanced angiogenesis. Clinical perspectiveO_LIInsufficient vascular repair increases the risk of acute cardiovascular events, something that is of particular importance in diabetes. C_LIO_LIA peptide derived from the extracellular matrix protein osteopontin (FOL-026) binds to the vascular endothelial growth factor (VEGF) co-receptor neuropilin-1 stimulating endothelial and vascular smooth muscle cell proliferation and migration as well as the formation of new vessels. C_LIO_LIBy mimicking the effects of VEGF FOL-026 may have therapeutical potential in conditions that require vascular repair and / or enhanced angiogenesis such as vascular complications to diabetes, peripheral artery disease and salvage of ischemic myocardium. C_LI

cell biology↗

bioRxiv2023

Disordered C-terminal domain drives spatiotemporal confinement of RNAPII to enhance search for chromatin targets

Efficient gene expression requires RNA Polymerase II (RNAPII) to find chromatin targets precisely in space and time. How RNAPII manages this complex diffusive search in 3D nuclear space remains largely unknown. The disordered carboxy-terminal domain (CTD) of RNAPII, which is essential for recruiting transcription-associated proteins, forms phase-separated droplets in vitro, hinting at a potential role in modulating RNAPII dynamics. Here, we use single-molecule tracking and spatiotemporal mapping in living yeast to show that the CTD is required for confining RNAPII diffusion within a subnuclear region enriched for active genes, but without apparent phase separation into condensates. Both Mediator and global chromatin organization are required for sustaining RNAPII confinement. Remarkably, truncating the CTD disrupts RNAPII spatial confinement, prolongs target search, diminishes chromatin binding, impairs pre-initiation complex formation, and reduces transcription bursting. This study illuminates the pivotal role of the CTD in driving spatiotemporal confinement of RNAPII for efficient gene expression.

cell biology↗

bioRxiv2023

LipidSIM: inferring mechanistic lipid biosynthesis perturbations from lipidomics with a flexible, low-parameter, systematic Markov Modeling framework

Lipid metabolism is a complex and dynamic system involving numerous enzymes at the junction of multiple metabolic pathways. Disruption of these pathways leads to systematic dyslipidemia, a hallmark of many pathological developments, such as nonalcoholic steatohepatitis and diabetes. Recent advances in computational tools can provide insights into the dysregulation of lipid biosynthesis, but limitations remain due to the complexity of lipidomic data, limited knowledge of interactions among involved enzymes, and technical challenges in standardizing across different lipid types. In this study, we present a low-parameter, biologically interpretable framework named Lipid Synthesis Investigative Markov model (LipidSIM), which models and predicts the source of perturbations in lipid biosynthesis from lipidomic data. LipidSIM achieves this by accounting for the interdependency between the lipid species via the lipid biosynthesis network and generates testable hypotheses regarding changes in lipid biosynthetic reactions. This feature allows the integration of lipidomics with other omics types, such as transcriptomics, to elucidate the direct driving mechanisms of altered lipidomes due to treatments or disease progression. To demonstrate the value of LipidSIM, we first applied it to hepatic lipidomics following Keap1 knockdown and found changes in mRNA expression of the lipid pathways were consistent with the LipidSIM-predicted fluxes. Second, we used it to study lipidomic changes following intraperitoneal injection of CCl4 to induce fast NAFLD/NASH development and the progression of fibrosis and hepatic cancer. Finally, to show the power of LipidSIM for classifying samples with dyslipidemia, we used a Dgat2-knockdown study dataset. Thus, we show that as it demands no a priori knowledge of enzyme kinetics, LipidSIM is a valuable and intuitive framework for extracting biological insights from complex lipidomic data.

bioinformatics↗

bioRxiv2023

Arabidopsis Transcription Factor WRKY45 Confers Cadmium Tolerance via Activating PCS1 and PCS2 Expression

Cadmium (Cd) has long been recognized as toxic pollutant to crops worldwide. The biosynthesis of glutathione-dependent phytochelatin plays crucial roles in the detoxification of Cd in plants. However, its regulatory mechanism remains elusive. Here, we revealed that Arabidopsis transcription factor WRKY45 confers Cd tolerance via promoting the expression of PC synthesis-related genes PCS1 and PCS2, respectively. Firstly, we found that Cd stress induces the transcript levels of WRKY45 and its protein abundance. Accordingly, in contrast to wild type Col-0, the increased sensitivity to Cd is observed in wrky45 mutant, while overexpressing WRKY45 plants are more tolerant to Cd. Secondly, quantitative real-time PCR revealed that the expression of AtPCS1 and AtPCS2 is stimulated in overexpressing WRKY45 plants, but decreased in wrky45 mutant. Thirdly, WRKY45 promotes the expression of PCS1 and PCS2, electrophoresis mobility shift assay analysis uncovered that WRKY45 directly bind to the W-box cis-element of PCS2 promoter. Lastly, the overexpression of WRKY45 in Col-0 leads to more accumulation of PCs in Arabidopsis, and the overexpression of PCS1 or PCS2 in wrky45 mutant plants rescues the phenotypes induced by Cd stress. In conclusion, our results show that AtWRKY45 positively regulate Cd tolerance in Arabidopsis via activating PCS1 and PCS2 expression. Environmental implicationAccumulation of cadmium (Cd) in soils poses a threat to crop productivity and food safety. It has been revealed that phytochelatin (PC) plays an essential role in plants to alleviate Cd toxicity, yet the regulatory mechanisms governing its expression remain unclear. We have demonstrated that the Arabidopsis transcription factor WRKY45 directly activates the expression of PCS1 and PCS2, which encode PC synthase, thereby increasing the content of PC and enhancing Arabidopsis tolerance to Cd stress. These findings offer insights into precise regulation strategies for crop Cd tolerance via modulation of WRKY45 homologue in crops.

molecular biology↗

bioRxiv2023

Well-ST-seq: cost-effective spatial transcriptomics at cellular level and high RNA capture efficiency

Spatial transcriptomic technologies are promising tools to reveal fine anatomical profiles of tissues. As for the methodologies based on barcoded probe arrays, improving the balance among probe barcoding complexity and cost, gene capture sensitivity, and spatial resolution can accelerate the spreading of spatial transcriptomic in basic science and clinical work. Here, based on miniaturized microfluidic and microarray technologies, we constructed a spatially cellular-level RNA-capture probe arrays. Owing to the predetermined and cost-effective probe fixation characteristics of the methodology, the consumable cost and fabrication time of the probe array can be reduced to $1.21/mm2 and approximately 2 hours, and the preparation process does not rely on large precision instruments. Moreover, the efficiency of the transcript captured by the probe array is even comparable to conventional single-cell RNA sequencing. Based on this technology, we achieved the spatial transcriptome expression mapping and gained insight into spatial cell heterogeneity of the mouse hippocampus.

genomics↗

bioRxiv2023

Intermediate basal cell population in prostate homeostasis and cancer initiation

Many glandular epithelia are mainly composed of basal cells and luminal cells, including the prostate gland. Adult prostate basal and luminal cells are independently self-sustained by unipotent stem cells that can reactivate multipotency under prostate inflammation and carcinogenesis contexts. However, the defined basal stem cell populations responsible for prostate regeneration and their cell fates in prostate homeostasis, inflammation and carcinogenesis remain unclear. Using a genetic proliferation tracer (ProTracer) system, we found that basal cells exhibited extensive cell loss and proliferation during androgen-mediated prostate regression and regeneration, respectively. A rare intermediate basal cell population that expresses luminal cell markers (Nkx3.1 and Pbsn) (termed Basal-B) and a large basal cell population (termed Basal-A) were identified in mouse prostates by single-cell RNA sequencing. Basal-B cells exhibited a greater capacity for organoid formation and luminal cell differentiation in vitro. Genetic lineage tracing using dual recombinases showed that prostate homeostasis and regeneration are not driven by specific basal cell types. Fate-mapping results showed that Basal-B cells had a greater tendency to generate luminal cells under bacteria-induced prostate inflammation. Deletion of Pten in basal cells resulted in Basal-A-to-Basal-B-to-luminal transition and prostatic intraepithelial neoplasia. Moreover, the human Basal-B-cell population was significantly increased in human benign prostate hyperplasia and prostatic intraepithelial neoplasia samples compared with normal prostate samples. This study identifies intermediate Basal-B cells as a potential stem cell population and provides genetic evidence of prostate basal cell lineage plasticity under physiological and pathological contexts.

developmental biology↗

bioRxiv2023

The initiation and maintenance of CHH methylation and its effects on gene expression are unique in maize

Trans-chromosomal interactions resulting in changes in DNA methylation during hybridization have been observed in several plant species. However, very little is known about the causes or consequences of these interactions. Here, we compared DNA methylomes of F1 hybrids that are mutant for a small RNA biogenesis gene, Mop1 (mediator of paramutation1) with that of their parents, wild type siblings, and backcrossed progeny in maize. Our data show that hybridization triggers global changes in both trans-chromosomal methylation (TCM) and trans-chromosomal demethylation (TCdM), most of which involved changes in CHH methylation. In more than 60% of these TCM differentially methylated regions (DMRs) in which small RNAs are available, no significant changes in the quantity of small RNAs were observed. Methylation at the CHH TCM DMRs was largely lost in the mop1 mutant, although the effects of this mutant varied depending on the location of the CHH DMRs. Interestingly, an increase in CHH at TCM DMRs was associated with enhanced expression of a subset of highly expressed genes and suppressed expression of a small number of lowly expressed genes. Examination of the methylation levels in backcrossed plants demonstrates that TCM and TCdM can be maintained in the subsequent generation, but that TCdM is more stable than TCM. Surprisingly, although increased CHH methylation in F1 plants did require Mop1, initiation of the changes in the epigenetic state of TCM DMRs did not require a functional copy of this gene, suggesting that initiation of these changes is not dependent on RNA-directed DNA methylation.

genomics↗

bioRxiv2023

BnIR: a multi-omics collaborative resource and tool platform for Brassica napus biological study

In the post-GWAS era, multi-omics techniques have shown great power and potential for candidate gene mining and functional genomics research. However, due to the lack of effective data integration and multi-omics analysis platforms, such techniques have not still been applied widely in rapeseed, an important oil crop worldwide. Here, we constructed a rapeseed multi-omics database (BnIR; http://yanglab.hzau.edu.cn/BnIR), which provides datasets of six omics including genomics, transcriptomics, variomics, epigenetics, phenomics and metabolomics, as well as numerous "variation-gene expression-phenotype" associations by using multiple statistical methods. In addition, a series of multi-omics search and analysis tools are integrated to facilitate the browsing and application of these datasets. BnIR is the most comprehensive multi-omics database for rapeseed so far, and two case studies demonstrated its power to mine candidate genes associated with specific traits and analyze their potential regulatory mechanisms. Short SummaryIn this study, we developed BnIR (http://yanglab.hzau.edu.cn/BnIR), a multi-omics database for rapeseed that integrates six omics datasets and "variation-gene expression-phenotype" associations. The database is equipped with a range of multi-omics tools for streamlined browsing and analysis. Through multiple case studies, we demonstrated BnIRs potential to identify candidate genes associated with specific traits and investigate their regulatory mechanisms.

bioinformatics↗

bioRxiv2023

Anthracyclines inhibit SARS-CoV-2 infection

Vaccines and drugs are two effective medical interventions to mitigate SARS-CoV-2 infection. Three SARS-CoV-2 inhibitors, remdesivir, paxlovid, and molnupiravir, have been approved for treating COVID-19 patients, but more are needed, because each drug has its limitation of usage and SARS-CoV-2 constantly develops drug resistance mutations. In addition, SARS-CoV-2 drugs have the potential to be repurposed to inhibit new human coronaviruses, thus help to prepare for future coronavirus outbreaks. We have screened a library of microbial metabolites to discover new SARS-CoV-2 inhibitors. To facilitate this screening effort, we generated a recombinant SARS-CoV-2 Delta variant carrying the nano luciferase as a reporter for measuring viral infection. Six compounds were found to inhibit SARS-CoV-2 at the half maximal inhibitory concentration (IC50) below 1 M, including the anthracycline drug aclarubicin that markedly reduced viral RNA-dependent RNA polymerase (RdRp)-mediated gene expression, whereas other anthracyclines inhibited SARS-CoV-2 by activating the expression of interferon and antiviral genes. As the most commonly prescribed anti-cancer drugs, anthracyclines hold the promise of becoming new SARS-CoV-2 inhibitors. IMPORTANCEMicrobial metabolites are a rich source of bioactive molecules. The best examples are antibiotics and immunosuppressants that have transformed the practice of modern medicine and saved millions of lives. Recently, some microbial metabolites were reported to have antiviral activity, including the inhibition of Zika virus and Ebola virus. In this study, we discovered several microbial metabolites that effectively inhibit SARS-CoV-2 infection, including anthracyclines that have also been shown to inhibit other viruses including Ebola virus through enhancing interferon responses, which indicates potentially broad antiviral properties of these microbial metabolites and can lead to the discovery of pan-antiviral molecules.

microbiology↗