Biology subjects

Yuan, S.

Publications and source records attributed to Yuan, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Chromatin remodeler BRG1 recruits huntingtin to repair DNA double-strand breaks in neurons

Persistent DNA double-strand breaks (DSBs) are enigmatically implicated in neurodegenerative diseases including Huntingtons disease (HD), the inherited late-onset disorder caused by CAG repeat elongations in Huntingtin (HTT). Here we combine biochemistry, computation and molecular cell biology to unveil a mechanism whereby HTT coordinates a Transcription-Coupled Non-Homologous End-Joining (TC-NHEJ) complex. HTT joins TC-NHEJ proteins PNKP, Ku70/80, and XRCC4 with chromatin remodeler Brahma-related Gene 1 (BRG1) to resolve transcription-associated DSBs in brain. HTT recruitment to DSBs in transcriptionally active gene- rich regions is BRG1-dependent while efficient TC-NHEJ protein recruitment is HTT-dependent. Notably, mHTT compromises TC-NHEJ interactions and repair activity, promoting DSB accumulation in HD tissues. Importantly, HTT or PNKP overexpression restores TC-NHEJ in a Drosophila HD model dramatically improving genome integrity, motor defects, and lifespan. Collective results uncover HTT stimulation of DSB repair by organizing a TC-NHEJ complex that is impaired by mHTT thereby implicating dysregulation of transcription-coupled DSB repair in mHTT pathophysiology. Highlights* BRG1 recruits HTT and NHEJ components to transcriptionally active DSBs. * HTT joins BRG1 and PNKP to efficiently repair transcription related DSBs in brain. * Mutant HTT impairs the functional integrity of TC-NHEJ complex for DSB repair. * HTT expression improves DSB repair, genome integrity and phenotypes in HD flies.

neuroscience↗

bioRxiv2024

Generation of High-fidelity Blastocyst-like Structures from Porcine Expanded Pluripotent stem cell via Chemically inducing cell plasticity

Understanding the mechanisms of blastocyst formation and implantation is crucial for advancing farm animal reproduction. However, research in this area is often hindered by the limited availability of embryos. In this study, we developed an efficient method to generate blastocyst-like structures (termed blastoids) from porcine expanded pluripotent stem cells (pEPSCs) through chemical induction with an efficiency up to 80%. These porcine blastoids closely resemble natural blastocysts in terms of morphology, cell composition, and single-cell transcriptomes. The tissue structures of the blastoids developed over time in culture, resembling the tissue morphology of gastrulation-stage embryos. This innovative approach not only provides a robust in vitro model for studying early embryogenesis in pigs but also holds the potential for improving reproductive efficiency and understanding the developmental processes of large farm animal species. The development of porcine blastoids represents a significant advancement in regenerative medicine and developmental biology.

cell 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

Global siRNA Screen Reveals Critical Human Host Factors of SARS-CoV-2 Multicycle Replication

Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased towards the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published datasets to reveal pathways supported by orthogonal datasets, including transcriptional regulation, epigenetic modifications, and MAPK signalling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 27 proteins that were determined to impact assembly and release. Additionally, a subset of proteins were tested across other coronaviruses revealing 17 potential pan-coronavirus targets. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry, and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo. These studies provide critical insight into the landscape of virus-host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals.

systems biology↗

bioRxiv2024

The protease ADAMTS5 controls ovarian cancer cell invasion, downstream of Rab25.

Ovarian cancer is the 3rd most common gynaecological malignancy worldwide, with a 5-year survival rate of less than 30% in the presence of metastasis. Metastatic progression is characterised by extensive remodelling of the extracellular matrix, primarily mediated by secreted matrix metalloproteinases, including members of the a disintegrin and metalloprotease with thrombospondin motif (ADAMTS) family. In particular, ADAMTS5 has been reported to be upregulated in ovarian malignant tumours compared to borderline and benign lesions, suggesting it might play a role in metastatic progression. Furthermore, it has been suggested that Rab25, a small GTPase of the Ras family, might upregulate ADAMTS5 expression in ovarian cancer cells. Here we demonstrated that Rab25 promotes ADAMTS5 expression, through the activation of the NF-{kappa}B signalling pathway. Furthermore, ADAMTS5 was necessary and sufficient to stimulate ovarian cancer cell migration through complex fibroblast-secreted matrices, while ADAMTS5 inhibition prevented ovarian cancer spheroid invasion in 3D systems. Finally, in ovarian cancer patients high ADAMTS5 expression correlated with poor prognosis. Altogether, these data identify ADAMTS5 as a novel regulator of ovarian cancer cell migration and invasion, suggesting it might represent a novel therapeutic target to prevent ovarian metastasis.

cancer biology↗

bioRxiv2024

User-friendly genome assembly and gene annotation pipelines for vertebrates

With the development of long reads sequencing technologies and assembly tools, high-quality genome assembly becomes routine in individual labs. In the past few years, numerous high-quality genome assemblies for various vertebrate individuals and species have been deposited in public databases. However, most of these genomes are not annotated for the protein-coding genes, the major working horse in cells, limiting their applications. This dilemma is caused by the reality that the existing easily-used tools cannot achieve accurate annotation, whereas accurate tools such as the NCBIs eukaryotic genome annotation pipeline are unavailable to individual labs due to the complexity of their use and their high demand for computing resources. Here, we developed an accurate and user-friendly gene annotation pipeline HRannot, enabling accurate annotation of both protein-coding genes and pseudogenes in vertebrate genomes using limited computing resources. Based on both homologous genes in related species and and RNA-seq data from the same species, HRannot is able to annotate both known and novel genes. HRannot outperforms all available well-regarded gene annotation tools, and is comparable or even better in some cases than the NCBIs gene annotation pipeline.

bioinformatics↗

bioRxiv2024

Comparative and population genomics analyses of eared pheasants inhabiting highly varying altitudes

Oxygen pressure varies dramatically with altitudes on Earth; however, humans and animals thrive at almost all altitudes. To better understand genetic basis underlying adaptation of closely related species to varying altitudes, we annotated and compared the genome of a white eared pheasant (WT) (Crossoptilon crossoptilon) inhabiting high altitudes and the genome of a brown eared pheasant (BR) (C. mantchuricum) inhabiting low altitudes. Moreover, we compared genetic variations in populations of WT and BR as well as of blue eared pheasants (BL) (C. auritum) inhabiting intermediate altitudes, and identified thousands of selective sweeps in each species. Intriguingly, the unique genes and pseudogenes in the two genomes converge on the same set of altitude adaptation-related pathways of four functional categories as genes in selective sweeps in each species. Thus, these species appear to adapt to highly varying altitudes by diverging selection on the same traits via loss-of-function mutations and fine-tuning genes in common pathways.

bioinformatics↗

bioRxiv2024

Large scale loss-of-function mutations during chicken evolution and domestication

Evolution and domestication are often driven by genetic innovations, yet the role of gene loss remains debated. Here, we present comparative genomic analyses of four indigenous chicken breeds from Yunnan Province, China and a reference red jungle fowl genome (GRCg6a). We identify extensive gene presence-absence variation and large numbers of pseudogenes, revealing highly dynamic gene repertoires among closely related chickens. By reconstructing ancestral gene content, we estimate that the common ancestor harbored at least 21,972 genes, of which 7,993 are dispensable. Each lineage has independently lost thousands of genes through both complete gene loss and pseudogenization. These loss-of-function events are non-random: pseudogenization mutations are biased toward gene termini, frequently fixed in populations, and enriched in specific biological pathways. Notably, patterns of gene loss recapitulate phylogenetic relationships, suggesting that loss-of-function mutations are shaped by selection rather than neutral drift. Analysis of four other chicken genomes assembled using PacBio HiFi reads draws the same conclusion. Thus, our results support a model in which large-scale loss-of-function mutations are a major driver of chicken evolution and domestication, consistent with the "less-is-more" hypothesis of adaptive evolution.

bioinformatics↗

bioRxiv2024

Simultaneous Prediction of Functional States and Types of cis-regulatory Modules Reveals Their Prevalent Dual Uses as Enhancers and Silencers

Our understanding of the precise locations of cis-regulatory elements (CRMs) in the genomes, as well as their functional types (enhancer or silencer), states (active or inactive) and target genes in various cell/tissue types of organisms remains limited, despite recent progresses. To address these challenges, we have recently developed a two-step strategy that first predicts a more complete map of CRMs in the genome, and then predicts the functional states of the CRMs. However, our initial approach lacked the ability to differentiate between the functional types of CRMs. Therefore, we utilized distinct features to simultaneously predict the functional types and states of the CRMs. Applying our method to 107 cell/tissue types with the minimum of required data available, we predicted 868,948 (73.8%) of the CRMs to be active as enhancers or silencers in at least one of these cell/tissue types. In 56 cell/tissue types with required data available for both enhancers and silencers, we predicted that 117,646 (14.8%) and 227,211 (28.6%) CRMs only functioned as enhancers (enhancer-predominant) and silencers (silencer-predominant), respectively, while 83,985 (10.6%) functioned both as enhancers and silencers (dual functional). Thus, both dual functional CRMs and silencers might be more prevalent than previously assumed. Most dual functional CRMs function either as enhancers or silencers in different cell/tissue types (Type I), while some have dual functions regulating different genes in the same cell/tissue types (Type II). Different types of CRMs display different lengths and TFBS densities, reflecting the complexity of their functions. Our two-step approach can accurately predict the functional types and states of CRMs using data of only five epigenetic marks in a cell/tissue type. Author SummaryCRMs function as enhancers and/or silencers to promote and repress, respectively, the transcription of genes in a spatiotemporal manner, thereby playing critical roles in virtually all biological processes. However, despite recent progress, the understanding of CRMs remains limited. Most existing methods are aimed to simultaneously predict the locations and functional states of enhancers in a given cell/tissue type, however, the accuracy of these one-step methods is low. We have recently developed a two-step strategy that first predicts locations of CRMs in the genome, and then predicts their functional states as enhancers in cell/tissue types with high accuracy. However, our initial approach was unable to differentiate between enhancers and silencers. Therefore, in this study, we employ two machine-learning models, so that we can simultaneously predict the functional states and types of our previously predicted 1.2M CRMs in various cell/tissue types. Applying the method to cell/tissue types with the data available, we categorize the CRMs into four types with distinct properties reflecting their functional complexity. Our results indicate that silencers and dual functional CRMs might be more prevalent than previously assumed. The precise prediction of CRM types and states provides opportunities to pinpoint their target genes, thus opening new avenues for research.

bioinformatics↗

bioRxiv2024

SLC13A2-transported citrate is a metabolic signal for PKM2 acetylation and degradation to suppress tumor growth

Background and aimsMetabolic reprogramming represents as a pivotal hallmark for cancer, but TCA cycle in tumorigenesis and progression has long been neglected. Solute carrier (SLC) transporters mediate the transport of TCA cycle intermediates across membrane, but their functions in cancer pathogenesis remains unclear. Approaches & ResultsUsing integrated analysis of solute carrier (SLC) transporters for TCA cycle intermediates, we found that SLC13A2 was consistently downregulated in hepatocellular carcinoma (HCC) cells and liver tissues from human patients and heterogeneous mouse models. Adeno-associated virus (AAV)-transduced liver-specific knockout or overexpression of SLC13A2 promoted or ameliorated HCC progression in the primary mouse model, demonstrating that SLC13A2 served as a protective factor during HCC pathogenesis. SLC13A2 inhibited HCC cell proliferation by decreasing mitochondrial function via suppressed oxygen consumption and ATP production. Combined with metabolic flux analysis, we found that SLC13A2 imported citrate, which secreted acetyl-CoA as a precursor for the acetylation of pyruvate kinase muscle isozyme M2 (PKM2), which led to its protein degradation. Decreased activity of pyruvate kinase depleted pyruvate for the TCA cycle, thus inhibiting amino acid synthesis and nucleotide metabolism. Additionally, a decrease in nuclear PKM2 protein transduced to reprogrammed gene transcription for cell proliferation and metabolism which is required for tumor growth. ConclusionsThis study revealed that citrate transported by SLC13A2 acts as a signal to disrupt metabolic homeostasis for tumor growth and suggests potential drug targets for HCC therapy. graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/591017v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@80c95eorg.highwire.dtl.DTLVardef@124750corg.highwire.dtl.DTLVardef@809ab4org.highwire.dtl.DTLVardef@12cbe74_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

SARS-CoV-2 infection activates inflammatory macrophages in vascular immune organoids

SARS-CoV-2 provokes devastating tissue damage by cytokine release syndrome and leads to multi-organ failure. Modeling the process of immune cell activation and subsequent tissue damage is a significant task. Organoids from human tissues advanced our understanding of SARS-CoV-2 infection mechanisms though, they are missing crucial components: immune cells and endothelial cells. This study aims to generate organoids with these components. We established vascular immune organoids from human pluripotent stem cells and examined the effect of SARS-CoV-2 infection. We demonstrated that infections activated inflammatory macrophages. Notably, the upregulation of interferon signaling supports macrophages role in cytokine release syndrome. We propose vascular immune organoids are a useful platform to model and discover factors that ameliorate SARS-CoV-2-mediated cytokine release syndrome.

immunology↗

bioRxiv2024

Impaired central pattern generators due to abnormal EPHA4 signaling leads to idiopathic scoliosis

Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we firstly reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited pronounced scoliosis during later stages of development, effectively recapitulating the IS phenotype. We observed that the epha4a mutants displayed defects in left-right coordination during locomotion, which arose from disorganized neural activation in these mutants. Our subsequent experiments indicated that the disruption of the central pattern generator (CPG) network, characterized by abnormal axon guidance of spinal cord interneurons, contributed to the disorganization observed in the mutants. Moreover, when knocked down efnb3b, the ligand for Epha4a, we observed similar CPG defects and disrupted left-right locomotion. These findings strongly suggested that ephrin B3-Epha4 signaling is vital for the proper functioning of CPGs, and defects in this pathway could lead to scoliosis in zebrafish. Furthermore, we identified two cases of IS in NGEF, a downstream molecule in the EPHA4 pathway. Collectively, our data provide compelling evidence that neural patterning impairments and disruptions in CPGs may underlie the pathogenesis of IS.

genetics↗

bioRxiv2024

Internalisation of integrin-bound extracellular matrix modulates invasive carcinoma cell migration

The interaction between cancer cells and the extracellular matrix (ECM) plays a pivotal role in tumour progression. While the extracellular degradation of ECM proteins has been well characterised, ECM endocytosis and its impact on cancer cell progression, migration and metastasis is poorly understood. ECM internalisation is increased in invasive breast cancer cells, suggesting it may support invasiveness. Here we developed a high-content screening assay to study ECM uptake. We identified that mitogen-activated protein kinase (MAPK) family members, MAP3K1 and MAPK11 (p38{beta}), and the protein phosphatase 2 (PP2) subunit PPP2R1A were required for the internalisation of ECM-bound 2{beta}1 integrin. Furthermore, 2{beta}1 integrin was necessary for macropinocytosis of soluble dextran, identifying it as a novel and targetable regulator of macropinocytosis in cancer. Moreover, disruption of 2 integrin, MAP3K1, MAPK11 and PP2R1A-mediated ECM internalisation significantly impaired cancer cell migration and invasion in 2D and 3D culture systems. Finally, 2{beta}1 integrin and MAP3K1 expression were significantly upregulated in pancreatic tumours and correlated with poor prognosis in pancreatic cancer patients. Strikingly, MAP3K1, MAPK11, PPP2R1A and 2 integrin expression were higher in chemotherapy-resistant tumours in breast cancer patients. Our results identified the 2{beta}1 integrin/p38 signalling axis as a novel regulator of ECM endocytosis, which drives invasive migration and tumour progression.

cancer biology↗

bioRxiv2024

Annotations of four high-quality indigenous chicken genomes identify more than one thousand missing genes in sub-telomeric regions with high G/C contents

BackgroundAlthough multiple chicken genomes have been assembled and annotated, the number of protein-coding genes in chicken genomes is still uncertain due to the low quality of these genome assemblies and limited resources used in gene annotations. ResultsTo fill the gap, we annotated our four recently assembled high-quality genomes of four indigenous chickens with distinct traits using a combination of RNA-seq- and homology-based approach. Our annotated genes in the four chickens recovered 51 of the 274 "missing" genes in birds in general and 36 of the 174 "missing" genes in chickens in particular. Intriguingly, based on deeply sequenced RNA-seq data collected in multiple tissues in each chicken breed, we found a total of 1,420 new protein-coding genes in the four chicken genomes, which were missed in the reference chicken genome annotations. These newly annotated genes (NAGs) tend to have high G/C contents and be located in sub-telomeric regions of almost all assembled chromosomes and some unplaced contigs. The NAGs showed tissue-specific expression and we were able to verify 39 (92.9%) of 42 randomly selected ones in various tissues of the four chicken breeds using RT-qPCR experiments. We found that most of the NAGs also are encoded in previously assembled chicken genomes. The NAGs form functional modules with homology-supported genes that are involved in many important biological pathways. We also identified numerous unique genes in each indigenous chicken genome that might be related to the unique traits of each breed. ConclusionThe ubiquitous presence of the NAGs in various chicken genomes indicate that they might play critical roles in chicken physiology. Counting these new genes, chicken genomes harbor more genes than originally thought.

bioinformatics↗

bioRxiv2023

High-quality genome assembly of a white eared pheasant individual and related functional and genetics data resources

White eared pheasant (WT), (Crossoptilon crossoptilon), inhibiting at high altitudes (3000[~]4,300 m), is a Galliformes bird native to the Qinghai, Sichuan, Yunnan and Tibet Province of China. Due to the difficulty of sequencing the precious species, there is no high-quality genome assembly for the species, hampering the understanding of their genetic mechanisms. To fill the gap, we sequenced and assembled a WT individual using Illumina short reads, PacBio long reads and Hi-C reads. With a contig N50 of 19.63 Mb, scaffold N50 of 29.59 Mb, total length of 1.02 Gb and BUSCO completeness of 97.2%, the assembly is highly complete. Evaluation shows that the assembly is at chromosome-level with only six gaps. Thus, our assembly provides a valuable genetic resource for the crossoptilon species. To further provide resources for gene annotation and population genetics analysis, we also sequenced transcriptomes of 20 tissues of the WT individual and re-sequenced another 10 individuals of WT. Our assembled WT genome and the sequencing data can be valuable resources to study the crossoptilon species.

bioinformatics↗

bioRxiv2023

WTAP is Transcriptionally Regulated by p65 and Promotes Inflammation through m6A Modification and Phase Separation

Emerging evidence has linked dysregulation of N6-methyladenosine (m6A) to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high m6A modification in a variety of hyperinflammatory states is p65-dependent, because Wilms tumor 1 associated protein (WTAP), a key component of the writer complex, is transcriptionally regulated by p65 and its overexpression can lead to higher m6A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of "writer" complex to nuclear speckles and the deposition of m6A marks onto transcriptionally active inflammatory transcripts, thereby accelerating proinflammatory response. Furthermore, myeloid deficiency of WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk-increasing mechanism, and interrupting the assembly of m6A writer complex by targeting the phase separation of WTAP to reduce the global m6A level may be a potential and promising therapeutic strategy for alleviating hyperinflammation.

immunology↗

bioRxiv2023

FBXO24 modulates mRNA alternative splicing and MIWI degradation and is required for normal sperm formation and piRNA production

Spermiogenesis is a critical, post-meiotic phase of male gametogenesis, in which the proper gene expression is essential for sperm maturation. However, the underlying molecular mechanism that controls mRNA expression in the round spermatids remains elusive. Here, we identify that FBXO24, an orphan F-box protein, is highly expressed in the testis of humans and mice and interacts with the splicing factors (SRSF2, SRSF3, and SRSF9) to modulate the gene alternative splicing in the round spermatids. Genetic mutation of FBXO24 in mice causes many abnormal splicing events in round spermatids, thus affecting a large number of critical genes related to sperm formation that were dysregulated. Further molecular and phenotypical analyses revealed that FBXO24 deficiency results in aberrant histone retention, incomplete axonemes, oversized chromatoid body (CB), and abnormal mitochondrial coiling along sperm flagella, ultimately leading to male sterility. In addition, we discovered that FBXO24 interacts with MIWI and SCF subunits and mediates the degradation of MIWI via K48-linked polyubiquitination. Furthermore, we show that FBXO24 depletion could lead to aberrant piRNA production in testes, which suggests FBXO24 is required for normal piRNA counts. Collectively, these data demonstrate that FBXO24 is essential for sperm formation and piRNA production by regulating mRNA alternative splicing and MIWI degradation during spermiogenesis.

developmental biology↗

bioRxiv2023

Immunities Specific to Both of the M Protein Ectodomain and RBD Synergize to Confer Cross-protection against SARS-CoV-2 Infections

The effectiveness of the prototypic SARS-CoV-2 vaccine largely decreased overtime against the emerging virus strains, necessitating the universal vaccine development. The most abundant structural membrane (M) protein is highly conserved in amino acid sequence, which arouses our research interests in developing a universal immunogen based on it. Serological analysis showed that IgG responses specific to its N-terminal peptides can be strongly detected in many serum samples from both convalescent patients and vaccinees receiving inactivated vaccines, indicating the potential existence of human B-cell epitopes in reactive peptides. Microneutralization assays showed that the N-terminal peptide S2M2-30-specific hyperimmune serum was capable of cross-neutralizing the authentic viruses including wild-type HKU-001a, B.1.617.2/Delta, and Omicron subvariant BQ.1.1, and synergized with RBD-specific serum in reinforcing antiviral activities. Strong S2M2-30-specific immunities elicited in hACE2-transgenic mice could effectively inhibit B.1.1.7/Alpha (UK) infections. Our results suggest the potentiality of conserved M peptides as vaccine targets for conferring cross-protections against sarbecoviruses.

immunology↗