Biology subjects

Zhang, C.

Publications and source records attributed to Zhang, C..

At least 379 records · Page 21Linked to original sources

bioRxiv2024

A novel bifunctional peptide VAMP mined from hemp seed protein hydrolysates improves glucose homeostasis by inhibiting intestinal DPP-IV and increasing the abundance of Akkermansia muciniphila

Discovery of new dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from natural protein resources capable of regulating glucose metabolism in type 2 diabetic populations has been a significant challenge. In this study, we constructed a molecular docking- and machine learning-aided DPP-IV inhibitory peptide library and combined a functional screening approach based on intestinal organoids to discover efficient and new DPP-IV-inhibiting peptides from hemp seed protein hydrolysates. A novel tetrapeptide, VAMP, was then identified to strongly inhibit DPP-IV (IC50=1.00 M in vitro), which competitively binds to DPP-IV and improves glucose metabolism in vivo with high safety by increasing active glucagon-like peptide-1 (GLP-1) levels in obese mouse models. Interestingly, VAMP specifically promoted the growth and abundance of intestinal Akkermansia muciniphila in vivo, at the same time, which was responsible for the improved intestinal barrier function and insulin resistance. Our study demonstrated that the novel bifunctional VAMP can effectively target the DPP-IV-GLP-1 axis and simultaneously regulate the abundance of the gut microbial A. muciniphila, to regulate glucose homeostasis, providing a promising nutraceutical and therapeutic tetrapeptide for hyperglycaemia treatment by targeting the gut-microbiata axis. TeaserVAMP improves glucose metabolism by increasing the active GLP-1 level and promoting the growth of A. muciniphila to improve intestinal barrier function.

molecular biology↗

bioRxiv2024

Phase transition of WTAP regulates m6A modification of interferon-stimulated genes

N6-methyladenosine (m6A) is the most prevalent modification of mRNA which controls diverse physiological processes. Although m6A modification has been reported to regulate type I interferon (IFN) responses by targeting the mRNA of IFN-{beta} and the interferon stimulated genes (ISGs), the detailed mechanism of how m6A methyltransferase complex (MTC) rapidly responds to conduct the modification on nascent mRNA during IFN-{beta} stimulation remains largely unclear. Here, we demonstrate that WTAP, the adaptor protein of m6A MTC, undergoes dephosphorylation-regulated phase transition from aggregates to liquid-like condensates under IFN-{beta} stimulation, thereby mediates m6A modification of a subset of ISG mRNAs to restrict their expression. The phase transition of WTAP promotes the interaction with nucleus-translocated transcription factor STAT1, which recruits MTC to the promoter regions of ISGs and directing the co-transcriptional m6A modification on ISG mRNAs. Collectively, our findings reveal a novel regulatory role of WTAP phase transition in manipulating signaling pathways and fine-tuning immune response by orchestrating dynamic m6A modification through the cooperation of transcription factors and MTC.

immunology↗

bioRxiv2024

The asymmetric expression of HSPA2 in blastomeres governs the first embryonic cell-fate decision

The first cell-fate decision is the process by which cells of an embryo take on distinct lineage identities for the first time, thus representing the beginning of developmental patterning. Here, we demonstrate that the molecular chaperone heat shock protein A2 (HSPA2), a member of the 70 kDa heat shock protein (HSP70) family, is asymmetrically expressed in the late 2-cell stage of mouse embryos. The knockdown of Hspa2 in one of the 2-cell blastomeres prevented its progeny predominantly toward the inner cell mass (ICM) fate. In contrast, the overexpression of Hspa2 in one of the two-cell blastomeres did not induce blastomeres to differentiate towards the ICM fate. Furthermore, we demonstrated that HSPA2 interacts with CARM1 and its levels correlate with ICM-associated genes and that it interacts with the CARM1. Collectively, our results identify HSPA2 as a critical early regulator of the first cell-fate decision in mammalian 2-cell embryos.

developmental biology↗

bioRxiv2024

The noncoding circular RNA circHomer1 regulates developmental experience-dependent plasticity in mouse visual cortex

Circular RNAs (circRNAs) are a class of closed-loop, single stranded RNAs whose expression is particularly enriched in the brain. Despite this enrichment and evidence that the expression of circRNAs are altered by synaptic development and in response to synaptic plasticity in vitro, the regulation by and function of the majority of circRNAs in experience-dependent plasticity in vivo remain unexplored. Here, we employed transcriptome-wide analysis comparing differential expression of both mRNAs and circRNAs in juvenile mouse primary visual cortex (V1) following monocular deprivation (MD), a model of experience-dependent developmental plasticity. Among the differentially expressed mRNAs and circRNAs following 3-day MD, the circular and the activity-dependent mRNA forms of the Homer1 gene, circHomer1 and Homer1a respectively, were of interest as their expression changed in opposite directions: circHomer1 expression increased while the expression of Homer1a decreased following 3-day MD. Knockdown of circHomer1 delayed the depression of closed-eye responses normally observed after 3-day MD. circHomer1-knockdown also led to a reduction in average dendritic spine size prior to MD but critically there was no further reduction after 3-day MD, consistent with impaired structural plasticity. circHomer1-knockdown also prevented the reduction of surface AMPA receptors after 3-day MD. Synapse-localized puncta of the AMPA receptor endocytic protein Arc increased in volume after MD but were smaller in circHomer1-knockdown neurons, suggesting that circHomer1 knockdown impairs experience-dependent AMPA receptor endocytosis. Thus, the expression of multiple circRNAs are regulated by experience-dependent developmental plasticity, and our findings highlight the essential role of circHomer1 in V1 synaptic development and experience-dependent plasticity. Significance StatementCircular RNAs (circRNAs) are a class of closed-loop RNAs formed through back-splicing of exon and/or intron junctions. Initially considered as byproducts of aberrant RNA splicing with limited function, recent studies have implicated circRNAs in various neurological disorders. Despite their abundant expression in the brain, the role of circRNAs in experience-dependent plasticity remains poorly understood. We conducted an in vivo transcriptome analysis of circRNAs whose expression was regulated by experience-dependent plasticity in the mouse visual cortex and highlight circHomer1, a circRNA derived from the Homer1 gene, as a circRNA critical for synaptic development and experience-dependent plasticity in vivo.

neuroscience↗

bioRxiv2024

Engineering Microglial Cells to Promote Spinal Cord Injury Recovery

Spinal cord injury (SCI) can result in irreversible damage, leading to lifelong paralysis for affected individuals. Microglias dual impact on neuronal regeneration after SCI, driven by their distinct roles at different stages, merits further study. We conducted a bioinformatic analysis of single-cell transcriptomes (scRNA), spatial transcriptomic (ST) data, and bulk RNA-seq data from Gene Expression Omnibus (GEO) datasets. The data were processed using R packages such as "Seurat", "DESeq2","limma" and "GSVA." Additionally, we utilized Gene Set Enrichment Analysis (GSEA) and the Enrichr web servers. Analysis of single-cell data and spatial transcriptomics has revealed notable changes in the microglial cell landscape in SCI. These changes encompass the inhibition of innate microglial cells, while reactive microglial cells exhibit pronounced reactive hyperplasia. Moreover, the TGF{beta} signaling pathway plays a crucial role in regulating the migration of innate microglial cells to enhance SCI recovery. However, reactive microglial cells exhibiting high Trem2 expression contribute to the neuroinflammatory response and can effectively modulate neural cell death in SCI. In particular, inhibiting Trem2 in reactive microglial cells not only reduces inflammation but also mitigates spinal cord injury, and enhancing the TGF{beta} signaling pathway. Whats more, the use of iPSC-derived microglial cells, which have demonstrated their capacity to augment the potential for replacing the functions of naive microglial cells, iPSC-derived microglia have the potential to replace the functions of naive microglial cells, holds significant promise in addressing SCI. Therefore, we posit that the engineering of microglial cells to promote the SCI recovery. The approach of inhibiting Trem2-mediated neuroinflammatory responses and transplanting iPSC-derived microglia with long-term TGF{beta} stimulation may offer potential improvements in SCI recovery.

neuroscience↗

bioRxiv2024

Blebs regulate phosphoinositides distribution and promote cell survival through the Septin-SH3KBP1-PI3K axis

Cells rely on substrate adhesion to activate diverse signaling pathways essential for survival. In the absence of proper adhesion, cells undergo anoikis, a form of programmed cell death. Poorly attached cells often exhibit rounded morphologies and form small round protrusions called blebs. While the role of blebs in amoeboid migration is well-documented, recent studies have highlighted their function in anoikis resistance with the help of curvature-recognized proteins. However, little is known about whether the most abundant membrane components-phospholipids function in blebs-facilitated cell survival. Here, we found enriched PI(3,4,5)P3 and diluted PI(4,5)P2 at the bleb membrane, compared to non-bleb plasma membrane regions. Our experimental results showed that both phosphoinositides (PIs) have restricted diffusion pattern between the bleb and non-bleb membranes. Subsequently, we reveal SH3KBP1 to play a crucial role in recruiting PI3K and organizing the Septin-SH3KBP1-PI3K complex at the bleb necks. This process then contributes to differential PIs distribution and anoikis resistance. These novel insights into PIs dynamics elucidate their role in cell blebbing, cancer cell behavior and metastasis, presenting potential targets for new therapeutic interventions. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/602823v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@63455eorg.highwire.dtl.DTLVardef@15f2092org.highwire.dtl.DTLVardef@535a26org.highwire.dtl.DTLVardef@43b48e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Oncogenic NOVA1 expression dysregulates alternative splicing in breast cancer

Neuro-Oncological Ventral Antigen 1 (NOVA1) is best known for its role in mediating an alternative splicing (AS) program in neurons, yet was first discovered as an antigen expressed in breast tumors, causing rare autoimmune reactions and paraneoplastic neurological disorders (PNDs). The PND model suggests a plausible role of the tumor antigen expression in tumor suppression, whereas it has emerged that NOVA may function as an oncogene in a variety of cancers. In addition, whether NOVA mediates AS in breast cancer remains unanswered. Here we examine the AS profiles of breast invasive carcinoma (BRCA) tumor samples and demonstrate that ectopic NOVA1 expression led to the activation of neuron-like splicing patterns in many genes, including exons targeted by NOVA in the brain. The splicing dysregulation is especially prevalent in cell periphery and cytoskeleton genes related to cell-cell communication, actin-based movement, and neuronal functions. We find that NOVA1-mediated AS is most prominent in Luminal A tumors and high NOVA1 expression in this subtype is associated with poorer prognosis. Our results suggest that ectopic NOVA1 in tumors has regulatory activity affecting pathways with high relevance to tumor progression and that this might be a more general mechanism for PND antigens.

cancer biology↗

bioRxiv2024

Illuminating microbial phosphorus cycling in deep-sea cold seep sediments using protein language models

Phosphorus is essential for life and critically influences marine productivity. Despite geochemical evidence of active phosphorus cycling in deep-sea cold seep ecosystems, the microbial processes involved remain poorly understood. Traditional sequence-based searches often fail to detect proteins with remote homology. To address this, we developed a protein language model (PLM) named LucaPCycle that integrates sequence and structural information. This PLM-based approach identified 4,606 new phosphorus-cycling protein families based on the non-redundant gene and genome catalogs from global cold seeps, substantially enhancing our understanding of their diversity, ecology, and function. Among previously unannotated sequences, we discovered three novel alkaline phosphatase families (ALP1, ALP2 and ALP3) that feature unique domain organizations and preserved enzymatic capabilities. These results highlight previously overlooked ecological importance of phosphorus cycling within cold seeps, corroborated by data from porewater geochemistry, metatranscriptomics, and metabolomics. We identified a previously unrecognized diversity of archaea contributing to organic phosphorus mineralization and inorganic phosphorus solubilization through various mechanisms. This includes ecologically significant groups such as Asgardarchaeota, anaerobic methanotrophic archaea (ANME), and Thermoproteota. Additionally, viruses can enhance their hosts (e.g., ANME) phosphorus utilization through the PhoR-PhoB regulatory system and PhnCDE transporter, indirectly influencing methane dynamics. Overall, our PLM-based functional predictions are capable of accessing previously hidden sequence spaces for microbial phosphorus cycling, and can be applied to other various ecosystems.

microbiology↗

bioRxiv2024

NSP4 mutation T492I drives rapid evolution of SARS-CoV-2 toward Omicron

T492I, a mutation encountered in SARS-CoV-2 nonstructural protein 4 (NSP4), enhances viral replication and alters nonstructural protein cleavage, causing potential evolutionary impacts. Through comprehensive comparative analyses based on evolve-and-resequence experiments of SARS-CoV-2 wild-type and Delta strains with or without T492I, we demonstrate that NSP4 T492I not only increases the mutation rate, but also accelerates the emergence of many mutations characteristic for Omicron variants. Accordingly, viral populations that evolved from ancestors with T492I, show Omicron-biased selective forces and increases in viral replication, infectivity, immune evasion capacity, potentials for cross-species transmission and receptor-binding affinity. Aside from enhanced replication, we observed stronger epistasis regarding viral replication and infectivity in T492I than in S N501Y and NSP6 {Delta}SGF; this facilitates the regulation of mutation types, which can drive fast evolution of Omicron specific mutations. Our results highlight the role of an important replication-enhancing mutation in regulating the evolutionary rates and mutational trends of SARS-CoV-2.

evolutionary biology↗

bioRxiv2024

Synergically enhanced anti-tumor immunity of in vivo CAR by circRNA vaccine boosting

Chimeric Antigen Receptor (CAR) T cell therapy has shown promise in treating hematologic malignancies. However, it is limited to individualized cell therapy and faces challenges, including high costs, extended preparation time, and limited efficacy against solid tumors. Here, we generated circular RNAs (circRNAs) encoding Chimeric Antigen Receptor (CAR) transmembrane proteins, referred to as circRNACAR, which mediated remarkable tumor killing in both T cells and macrophages. In addition, macrophages exhibited efficient phagocytosis of tumor cells and pro-inflammatory polarization induced by circRNACAR in vitro. We demonstrated that circRNACAR, delivered with immunocyte-tropic lipid nanoparticles (LNPs), significantly inhibited tumor growth, improved survival rates and induced a pro-inflammatory tumor microenvironment in mice. Importantly, the combination of circRNAAnti-HER2-CAR and circRNA-based cancer vaccines encoding the corresponding transmembrane HER2 antigen, termed circRNAHER2, exhibited synergistically enhanced anti-tumor activity. This proof-of-concept study demonstrated that the combination of circRNA-based in vivo CAR and vaccines, termed in vivo CAR-VAC, holds the potential to become an upgraded off-the-shelf immunotherapy.

immunology↗

bioRxiv2024

Unsilenced inhibitory cortical ensemble gates remote memory retrieval

Acquired information can be consolidated to remote memory for storage but persists in a dormant state until its retrieval. However, it remains unknown how dormant memory is reactivated. Using a combination of simultaneous two-photon calcium imaging and holographic optogenetics in the anterior cingulate cortex (ACC) in vivo, we discover a subset of GABAergic neurons that are specifically associated with dormant memory retrieval. These interneurons display persistent activity and inter-neuronal synchronization at the remote memory stage. In the absence of natural contextual cues, directly activating these interneurons reliably recalls cortical ensembles relevant to remote memory retrieval with context specificity. Conversely, targeted volumetric inactivation of these interneurons suppresses context-induced memory retrieval. Our results reveal an unexpected role of unsilenced inhibitory cortical ensembles in causally gating the retrievability of dormant remote memory.

neuroscience↗

bioRxiv2024

Deep mutational scanning reveals sequence to function constraints for SWEET family transporters

Protein science is entering a transformative phase enabled by deep mutational scans that provide an unbiased view of the residue level interactions that mediate function. However, it has yet to be extensively used to characterize the mutational and evolutionary landscapes of plant proteins. Here, we apply the method to explore sequence-function relationships within the sugar transporter AtSWEET13. DMS results describe how mutational interrogation throughout different regions of the protein affects AtSWEET13 abundance and transport function. Our results identify novel transport-enhancing mutations that are validated using the FRET sensor assays. Extending DMS results to phylogenetic analyses reveal the role of transmembrane helix 4 (TM4) which makes the SWEET family transporters distinct from prokaryotic SemiSWEETs. We show that transmembrane helix 4 is intolerant to motif swapping with other clade-specific SWEET TM4 compositions, despite accommodating single point-mutations towards aromatic and charged polar amino acids. We further show that the transfer learning approaches based on physics and ML based In silico variant prediction tools have limited utility for engineering plant proteins as they were unable to reproduce our experimental results. We conclude that DMS can produce datasets which, when combined with the right predictive computational frameworks, can direct plant engineering efforts through derivative phenotype selection and evolutionary insights.

plant biology↗

bioRxiv2024

Frontal-posterior loop integrating captured attention into visual consciousness in the human brain

We usually perceive what we are attending to. How goal-directed attention contributes to conscious perception remains yet elusive. Here we combined a novel psychophysical paradigm with intracranial electroencephalography data to investigate this issue in the human brain. Relative to unattended conditions, goal-directed attention modulated early activity and inter-regional connectivity, even though this part of attention failed to predict image detectability. Later, the coupling between the frontal and posterior brain got established and maintained but the signals exchanged did not inform fine-grained image contents but instead reflect success or failure of attentional capture. This part of captured attention proportionally predicted image detectability. These results attribute consciousness to attention-based coupling between the frontal and posterior brain as a whole, rather than activity of either part alone.

neuroscience↗

bioRxiv2024

TCRfinder: Improved TCR virtual screening for novel antigenic peptides with tailored language models

Accurate modeling of T-cell receptor (TCR) and peptide interactions is essential for immunoreaction elucidation and T-cell-based immunotherapeutic developments. We developed TCRfinder, a novel deep-learning architecture for TCR-peptide binding prediction and virtual screening. Large-scale benchmark experiments demonstrated a robust capability of TCRfinder in distinguishing interacting and non-interacting TCRs for unseen peptides, with accuracy significantly beyond current state-of-the-art methods. Furthermore, TCRfinder recognizes tumor neoantigen mutations from wild-type antigens of given TCRs, with a success rate nearly 50% higher than the best of existing methods. Detailed data analyses showed that the major advantage of TCRfinder lies in the specially trained TCR and peptide language models tailored with iterative attention network architecture, which can precisely reveal physical interaction patterns of cross-chain atoms and substantially enhance the precision of TCR-peptide interaction predictions. The open-source TCRfinder program can help facilitate large-scale deployment of high-quality TCR and neoantigen virtual screening, offering exciting potential for personalized TCR-based immunotherapies.

bioinformatics↗

bioRxiv2024

Loss of neurofibromin accelerates uveal and dermal melanoma formation driven by GNAQ

Neurofibromin is a very large and complex tumor suppressor, whose loss can synergize with other MAPK pathway mutations to promote melanoma in the skin. In this paper, we investigated whether NF1 loss has a role in other melanomas, such as those that form in the dermis or eye (uveal tract). We found that heterozygous 17q11.2 loss that includes the NF1 locus is an uncommon, but recurrent phenomenon in human dermal and uveal melanomas described previously. We studied the effects of Nf1 haploinsufficiency in mice expressing oncogenic GNAQQ209L in melanocytes and Schwann cells of peripheral nerves using the Plp1-creERT transgene, with tamoxifen given at 5 weeks of age. Nf1 haploinsufficiency accelerated dermal and uveal melanoma formation. We studied the effects of Nf1 loss in these melanomas using RNAseq. Many of the differentially expressed genes were homologous to genes whose expression correlates with prognosis in human uveal melanoma. Of particular interest was the up-regulation of cAMP signaling and its connection to protein kinase A, which is mutant in malignant melanotic nerve sheath tumors (MMNSTs). An unexpected finding was that oncogenic GNAQ was sufficient by itself to drive peripheral nerve sheath-like neoplasms in the mice. Hence, these studies reveal new insight into both melanocyte and Schwann cell transformation.

cancer biology↗

bioRxiv2024

High efficient chromatin conformation capture without pre-enrichment (HiChew) in single cells

This study presents HiChew, a cutting-edge technique for high-efficiency chromatin conformation capture in single cells, without the need for pre-enrichment. This unique approach minimizes the risk of cell or DNA loss. When compared to Dip-C, HiChew captures valid pairs with 4-8 times more efficiency, reducing wastage and saving significant sequencing budget. Furthermore, HiChew delivers a lower false positive ratio, ensuring data accuracy. It also achieves more contacts per cell, enhancing resolution in single cell. HiChews superior performance not only enhances single-cell Hi-C but also streamlines conventional Hi-C, making it more robust than conventional HiC methods. This study also unveils a fascinating mechanism of gene activation in the B compartment of chromatin, providing insight into the elusive aspect of gene expression within this region.

genomics↗

bioRxiv2024

Exploring DNA movement through the application of droplet based high efficient chromatin conformation capture (DropHiChew) and loop velocity

This study presents a novel approach to understanding DNA movement dynamics through the development of a droplet-based, high-efficient chromatin conformation capture method, known as DropHiChew, and a new algorithm, loop velocity. DropHiChew, a user-friendly and cost-effective technique, employs the 10X single-cell systems allowing for easy experimental implementation. The loop velocity algorithm, on the other hand, enables the estimation of the speed and direction of cell development, providing a dynamic perspective on chromatin movement. Even with shallow sequencing, our loop velocity algorithm accurately gauges the trajectory of DNA motion and cellular states. The combined use of DropHiChew and loop velocity offers potential for a wide array of applications in future chromatin capture studies, including disease modeling, cellular differentiation studies, and developmental biology.

genomics↗

bioRxiv2024

InterLabelGO+: Unraveling label correlations in protein function prediction

MotivationAccurate protein function prediction is crucial for understanding biological processes and advancing biomedical research. However, the rapid growth of protein sequences far outpaces the experimental characterization of their functions, necessitating the development of automated computational methods. ResultsWe present InterLabelGO+, a hybrid approach that integrates a deep learning-based method with an alignment-based method for improved protein function prediction. InterLabelGO+ incorporates a novel loss function that addresses label dependency and imbalance and further enhances performance through dynamic weighting of the alignment-based component. A preliminary version of InterLabelGO+ achieved a strong performance in the CAFA5 challenge, ranking 6th out of 1,625 participating teams. Comprehensive evaluations on large-scale protein function prediction tasks demonstrate InterLabelGO+s ability to accurately predict Gene Ontology terms across various functional categories and evaluation metrics. Availability and ImplementationThe source code and datasets for InterLabelGO+ are freely available on GitHub at https://github.com/QuanEvans/InterLabelGO. The software is implemented in Python and PyTorch, and is supported on Linux and macOS. Contactlydsf@umich.edu (LF) and zcx@umich.edu (CZ)

bioinformatics↗