Biology subjects

Deng, Q.

Publications and source records attributed to Deng, Q..

At least 73 records · Page 4Linked to original sources

bioRxiv2023

Early microbial intervention reduces diarrhea while improves later milk production in newborn calves

The rumen of neonatal calves is not well-developed and exhibits limited functionality. Therefore, the establishment of intestinal microbiota may play an instrumental role in their health and performance, but it has been rarely explored. Thus, we aim to explore the temporal colonization of the gut microbiome and the potential benefits of early microbial intervention in newborn calves. We followed up on the temporal dynamics of the gut microbiome and plasma metabolome in 36 newborn calves during the first two months of life and established their relationships with their health status and performance. We also evaluated whether microbiota transplantation (MT) could influence their phenotypes by modulating metabolism and its impact on later milk production performance.We showed that the composition and ecological interactions of the gut microbiome are likely to reach maturity one month after birth. Temporal changes in the gut microbiome of newborn calves are widely associated with changes in their physiological statuses, such as growth and fiber digestion. Importantly, we observed that MT reshapes the gut microbiome of newborns by altering the abundance and interaction of Bacteroides species, as well as amino acid pathways, such as arginine biosynthesis. Two-year follow-up of those calves further showed that MT improves their later milk production. Notably, MT improves fiber digestion, antioxidant capacity of newborns while reducing diarrhea. MT also contributes to significant changes in the metabolomic landscape, and with putative causal mediation analysis, we suggest that altered gut microbial composition in newborns may influence physiological status through microbial-derived metabolites. The data from the study may help develop strategies to manipulate the gut microbiota during early life, which may be significantly relevant to the health and production of newborn calves. HIGHLIGHTSO_LIThe gut microbial composition and ecological interaction in newborn calves reach maturity one month after birth C_LIO_LITemporal shifts in the gut microbiome of newborn calves are associated with phenotypic changes, including growth, digestion, and antioxidative capacity C_LIO_LIEarly microbial intervention in newborn calves reduces diarrhea while improving later milk production C_LIO_LIThe gut microbial impact on newborn calves is mediated by plasma metabolites C_LI

microbiology↗

bioRxiv2022

Reconstructing the formation of Hmong-Mien genetic fine-structure

The linguistic, historical, and subsistent uniqueness of Hmong-Mien (HM) speakers offers a wonderful opportunity to investigate how these factors impact the genetic structure. Nevertheless, the genetic differentiation among HM-speaking populations and the formation process behind are far from well characterized in previous studies. Here, we generated genome-wide data from 67 Yao ethnicity samples and analyzed them together with published data, particularly by leveraging haplotype-based methods. We identify that the fine-scale genetic substructure of HM-speaking populations corresponds better to linguistic classification than to geography, while the parallel of serial founder events and language differentiations can be found in West Hmongic speakers. Multiple lines of evidence indicate that ~500-year-old GaoHuaHua individuals are most closely related to West Hmongic-speaking Bunu. The excessive level of the genetic bottleneck of HM speakers, especially Bunu, is in agreement with their long-term practice of slash-and-burn agriculture. The inferred admixture dates in most of the HM-speaking populations overlap the reign of the Ming dynasty (1368 - 1644 CE). Besides the common genetic origin of HM speakers, their external ancestry majorly comes from neighboring Han Chinese and Kra-Dai speakers in South China. Conclusively, our analysis reveals the recent isolation and admixture events that contribute to the fine-scale genetic formation of present-day HM-speaking populations underrepresented in previous studies.

genomics↗

bioRxiv2022

Atypical peripheral actin band formation via overactivation of RhoA and Non-muscle myosin II in Mitofusin 2 deficient cells

Cell spreading and migration play central roles in many physiological and pathophysiological processes. We have previously shown that MFN2 regulates the migration of human neutrophillike cells via suppressing Rac activation. Here, we show that in mouse embryonic fibroblasts, MFN2 suppresses RhoA activation and supports cell polarization. After the initial spreading period, the wild-type cells polarize and migrate, whereas the Mfn2-/- cells maintain a circular shape. Increased cytosolic Ca2+ resulting from the loss of Mfn2 is directly responsible for this phenotype, which can be rescued by expressing an artificial tether to bring mitochondria and ER to close vicinity. Elevated cytosolic Ca2+ activates Ca2+/calmodulin-dependent protein kinase II, RhoA, and Myosin light-chain kinase, causing an over-activation of non-muscle myosin II and a formation of a prominent F-actin ring at the cell periphery and increased cell contractility. The formation of the peripheral actin band alters cell physics and is dependent on substrate rigidity. Our results provide a novel molecular basis to understand how MFN2 regulates distinct signaling pathways in different cells and tissue environments, which is instrumental in understanding and treating MFN2-related diseases.

cell biology↗

bioRxiv2022

Golgi-dependent Reactivation and Regeneration of Quiescent Neural Stem Cells

The ability of stem cells to switch between quiescent and proliferative states is crucial for maintaining tissue homeostasis and regeneration. In Drosophila, quiescent neural stem cells (qNSCs) extend a primary protrusion, which is removed prior to NSC reactivation. Here, we have unravelled that qNSC protrusions can be regenerated upon injury. This regeneration process relies on the Golgi apparatus which acts as the major acentrosomal microtubule-organizing centre in qNSCs. A Golgi-resident GTPase Arf1 and its guanine-nucleotide exchange factor Sec71 promote NSC reactivation and regeneration via the regulation of microtubule growth. Arf1 physically associates with its new effector Mini Spindles (Msps)/XMAP215, a microtubule polymerase. Finally, Arf1 functions upstream of Msps to target the cell-adhesion molecule E-cadherin to NSC-neuropil contact sites during NSC reactivation. Our findings have established Drosophila qNSCs as a new regeneration model and identified a novel Arf1/Sec71-Msps pathway in the regulation of microtubule growth and NSC reactivation.

cell biology↗

bioRxiv2022

Single-cell transcriptional profiling reveals cellular and molecular divergence in human maternal-fetal interface

Placenta play essential role in successful pregnancy, as the most important organ connecting and interplaying between mother and fetus. However, the cellular and molecular characteristics of fetal origin and maternal origin cell populations within the fetomaternal interface still is poorly understood. Here, we profiled the transcriptomes of single cells with well-defined maternal-fetal origin that consecutively localized from fetal section (FS), middle section (Mid_S) to maternal section (Mat_S) within the human full-term placenta. Then, we initially identified the cellular and molecular heterogeneity of cytotrophoblast cell (CTB) and stromal cell (STR) with the spatial location and fetal/maternal origin, also highlighted STR cells from fetal origins showed greater proliferation ability in Mat_S compared to cells from FS or Mid_S. Further, by integrating analysis with the first-trimester placental single cell transcriptome data, we revealed that a subpopulation of trophoblast progenitor-like cells (TPLCs) existed in the full-term placenta and mainly distributed in Mid_S, with high expression of pool of putative cell surface makers and unique molecular features. Moreover, through the extravillous cytotrophoblast (EVT) subsets differentiation trajectory and regulation network analysis, we proposed a putative key transcription factor PRDM6 that promoted the differentiation of endovascular extravillous trophoblast cells (enEVT). Finally, based on the integrated analyses of single cell transcriptional profiling of preeclampsia (PE) and match-trimester normal placenta, we highlighted the defective EVT subgroup composition and down-regulation of PRDM6 may lead to an abnormal enEVT differentiation process in PE. Together, our study offers important resources for better understanding of human placenta, stem cell-based therapy as well as PE, and provides new insights on the study of tissue heterogeneity, the clinical prevention and control of PE as well as the maternal-fetal interface.

developmental biology↗

bioRxiv2022

SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a novel mechanism by which the SARS-CoV-2 virus co-opts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-{beta}. We reveal that the SARS-CoV-2 encoded Non-Structural Protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-{beta} production, leading to reduced viral infection. Our findings reveal a new target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

microbiology↗

bioRxiv2021

Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody

The effectiveness of SARS-CoV-2 vaccines and therapeutic antibodies has been limited by the continuous emergence of viral variants, and by the restricted diffusion of antibodies from circulation into the sites of respiratory virus infection. Here, we report the identification of two highly conserved regions on Omicron variant RBD recognized by broadly neutralizing antibodies. Based on this finding, we generated a bispecific single-domain antibody that was able to simultaneously and synergistically bind these two regions on a single Omicron variant RBD as revealed by Cryo-EM structures. This inhalable antibody exhibited exquisite neutralization breadth and therapeutic efficacy in mouse models of SARS-CoV-2 infections. The structures also deciphered an uncommon cryptic epitope within the spike trimeric interface that may have implications for the design of broadly protective SARS-CoV-2 vaccines and therapeutics.

immunology↗

bioRxiv2021

Cell transcriptomic atlas of the non-human primate Macaca fascicularis

Studying tissue composition and function in non-human primates (NHP) is crucial to understand the nature of our own species. Here, we present a large-scale single-cell and single-nucleus transcriptomic atlas encompassing over one million cells from 43 tissues from the adult NHP Macaca fascicularis. This dataset provides a vast, carefully annotated, resource to study a species phylogenetically close to humans. As proof of principle, we have reconstructed the cell-cell interaction networks driving Wnt signalling across the body, mapped the distribution of receptors and co-receptors for viruses causing human infectious diseases and intersected our data with human genetic disease orthologous coordinates to identify both expected and unexpected associations. Our Macaca fascicularis cell atlas constitutes an essential reference for future single-cell studies in human and NHP.

cell biology↗

bioRxiv2021

Smart3-ATAC: a highly sensitive method for joint accessibility and full-length transcriptome analysis in single cells

Joint single-cell measurements of gene expression and DNA regulatory element activity holds great promise as a tool to understand transcriptional regulation. Towards this goal we have developed Smart3-ATAC, a highly sensitive method which allows joint mRNA and chromatin accessibility analysis genome wide in single cells. With Smart3-ATAC, we are able to obtain the highest possible quality measurements per cell. The method combines transcriptomic profiling based on the highly sensitive Smart-seq3 protocol on cytosolic mRNA, with a novel low-loss single-cell ATAC (scATAC) protocol to measure chromatin accessibility. Compared to current droplet multiome methods, the yield of both the scATAC protocol and mRNA-seq protocol is markedly higher.

systems biology↗

bioRxiv2021

RORA regulates neutrophil migration and activation in zebrafish

Neutrophil migration and activation are essential for defense against pathogens. However, this process may also lead to collateral tissue injury. We used microRNA overexpression as a platform and discovered protein-coding genes that regulate neutrophil migration. Here we show that miR-99 decreased the chemotaxis of zebrafish neutrophils and human neutrophil-like cells. In zebrafish neutrophils, miR-99 directly targets the transcriptional factor RAR-related orphan receptor alpha (roraa). Inhibiting ROR, but not the closely related ROR{gamma}, reduced chemotaxis of zebrafish and primary human neutrophils without causing cell death, and increased susceptibility of zebrafish to bacterial infection. Expressing a dominant-negative form of Ror or disrupting the roraa locus specifically in zebrafish neutrophils reduced cell migration. At the transcriptional level, ROR regulates transmembrane signaling receptor activity and protein phosphorylation pathways. Our results, therefore, reveal previously unknown functions of miR- 99 and ROR in regulating neutrophil migration and anti-microbial defense.

cell biology↗

bioRxiv2021

Allele-resolved single-cell multi-omics uncovers the dynamics and transcriptional kinetics of X-chromosome upregulation

X-chromosome inactivation (XCI) and upregulation (XCU) are the major opposing chromosome-wide modes of gene regulation that collectively achieve dosage compensation in mammals, but the regulatory link between the two remains elusive. Here, we use allele-resolved single-cell RNA-seq combined with chromatin accessibility profiling to finely dissect the separate effects of XCI and XCU on RNA levels during mouse development. We uncover that balanced X dosage is flexibly attained through expression tuning by XCU in a sex- and lineage-specific manner along varying degrees of XCI and across developmental and cellular states. Male blastomeres achieve XCU upon zygotic genome activation while females experience two distinct waves of XCU, upon imprinted- and random XCI, and ablation of Xist impedes female XCU. Contrary to widely established models of mammalian dosage compensation, naive female embryonic cells carrying two active X chromosomes do not exhibit upregulation but express both alleles at basal level, yet collectively exceeding the RNA output of a single hyperactive allele. We show, in vivo and in vitro, that XCU is kinetically driven by X-specific modulation of transcriptional burst frequency, coinciding with increased compartmentalization of the hyperactive allele. Altogether, our data provide unprecedented insights into the dynamics of mammalian XCU, prompting a revised model of the chain in events of allelic regulation by XCU and XCI in unitedly achieving stable cellular levels of X-chromosome transcripts.

genomics↗

bioRxiv2021

Tumour Suppressor Parafibromin/Hyrax Governs Cell Polarity and Centrosome Assembly in Neural Stem Cells

Neural stem cells (NSCs) divide asymmetrically to balance their self-renewal and differentiation, an imbalance in which can lead to NSC overgrowth and tumour formation. The functions of Parafibromin, a conserved tumour suppressor, in the nervous system are not established. Here, we demonstrate that Drosophila Parafibromin/Hyrax (Hyx) inhibits NSC overgrowth by governing cell polarity. Hyx is essential for the apicobasal polarization of NSCs, through its role in the asymmetric distribution of polarity proteins. hyx depletion results in the symmetric division of NSCs, leading to the formation of supernumerary NSCs in the larval brain. Importantly, we show that human Parafibromin can fully rescue NSC overgrowth and cell polarity defects in Drosophila hyx mutant brains. We have also discovered a novel role for Hyx in regulating the formation of interphase microtubule-organizing center and mitotic spindles in NSCs. Moreover, Hyx is required for the proper localization of a key centrosomal protein, Polo, and the microtubule-binding proteins Msps and D-TACC in dividing NSCs. Furthermore, Hyx directly regulates the polo expression in vitro. Altogether, our study provides the first evidence that the brain tumour suppressor-like role and polarity establishing functions of Hyx are mediated by its role in regulating microtubule growth and centrosomal assembly. The new paradigm that Parafibromin orchestrates cell polarization by regulating centrosomal assembly may be relevant to future studies on Parafibromin/HRPT2-associated cancers.

developmental biology↗

bioRxiv2021

Immune microenvironment subtypes and association with tumor cell mutations and antigen expression in follicular lymphoma.

Follicular lymphoma (FL) is a B-cell lymphoma with a complex tumor microenvironment that is rich in non-malignant immune cells. We applied single-cell RNA-sequencing to characterize the diverse tumor and immune cell populations of FL and identified major phenotypic subsets of FL T-cells including a novel cytotoxic CD4 T-cell population. Their relative proportions of T-cells defined four major FL subtypes, characterized by differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced antigen presentation on FL cells. In turn, expression of MHC class II genes by FL cells was associated with significant differences in the proportions and targetable immunophenotypic characteristics. This provides a classification framework of the FL microenvironment, their association with FL genotypes and antigen presentation, and informs different potential immunotherapeutic strategies based upon tumor cell MHC class II expression. Statement of significanceWe have characterized the FL-infiltrating T-cells, identified cytotoxic CD4 T-cells as an important component, showed that the abundance of these T-cell populations is associated with tumor-cell-intrinsic characteristics, and identified sets of targetable immune checkpoints on T-cells that differed between FLs with normal versus low antigen presentation.

cancer biology↗

bioRxiv2021

Single-cell analysis reveals MHCII expressing keratinocytes in pressure ulcers with worse healing outcomes

Pressure ulcer (PU) is a chronic wound often seen in spinal cord injury patients and other bed-bound individuals, particularly in the elderly population. Despite its association with high mortality, the pathophysiology of PU remains poorly understood. Here, we compared single-cell transcriptomic profiles of human epidermal cells from PU wound edges with those from uninjured skin and acute wounds (AWs) in healthy donors. We identified significant shifts in the cell composition and gene expression patterns in PU. In particular, we found that major histocompatibility complex class II (MHCII) expressing keratinocytes were enriched in patients with worse healing outcomes. Furthermore, we showed that the IFN{gamma} in PU-derived wound fluid could induce MHCII expression in keratinocytes and that these wound fluid-treated keratinocytes inhibited autologous T cell activation. In line with this observation, we found that T cells from PUs enriched with MHCII+ keratinocytes produced fewer inflammatory cytokines. Overall, our study provides a high-resolution molecular map of human PU compared to AW and intact skin, providing new insights into PU pathology and the future development of tailored wound therapy.

genomics↗

bioRxiv2021

Single-nuclei transcriptomes from human adrenal gland reveals distinct cellular identities of low and high-risk neuroblastoma tumors.

Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. We studied single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland. We compared tumor cell populations with embryonic mouse sympatho-adrenal derivatives, and post-natal human adrenal gland. We provide evidence that low and high-risk neuroblastoma have different cell identities, representing two disease entities. Low-risk neuroblastoma presents a transcriptome that resembles sympatho- and chromaffin cells, whereas malignant cells enriched in high-risk neuroblastoma resembles an unknown subtype of TRKB+ cholinergic progenitor population identified in human post-natal gland. Analyses of these populations revealed different gene expression programs for worst and better survival in correlation with age at diagnosis. Our findings reveal two cellular identities and a composition of human neuroblastoma tumors reflecting clinical heterogeneity and outcome.

cancer biology↗

bioRxiv2021

Multiomics Interrogation into HBV (Hepatitis B Virus)-Host Interaction Reveals Novel Coding potential in Human Genome, and Identifies Canonical and Non-canonical Proteins as Host Restriction Factors against HBV

Hepatitis B Virus constitutes a major threat to global public health. Current understanding of HBV-host interaction is yet limited. Here, ribosome profiling, quantitative mass spectrometry and RNA-sequencing are conducted on a recently established HBV replication system. We have identified multiomic DEGs (differentially expressed genes) that HBV orchestrated to remodel host proteostasis networks. Our multiomics interrogation revealed that HBV induced significant changes in both transcription and translation of 35 canonical genes including PPP1R15A, PGAM5 and SIRT6, as well as the expression of at least 15 non-canonical ORFs including ncPON2 and ncGRWD1, thus revealing an extra coding potential of human genome. Overexpression of these five genes but not the enzymatically deficient SIRT6 mutants suppressed HBV replication while knockdown SIRT6 had opposite effect. Furthermore, the expression of SIRT6 was down-regulated in patients, cells or animal models of HBV infection. Mechanistic study further indicated that SIRT6 directly binds to mini-chromosome and deacetylates histone H3 lysine 9 (H3K9ac) and histone H3 lysine 56 (H3K56ac), and chemical activation of endogenous SIRT6 with MDL800 suppressed HBV infection in vitro and in vivo. By generating the first multiomics landscape of host-HBV interaction, our work is thus opening a new avenue to facilitate therapeutic development against HBV infection.

microbiology↗

bioRxiv2021

Oncofusion-driven de novo enhancer assembly promotes malignancy in Ewing sarcoma via aberrant expression of the stereociliary protein LOXHD1

Ewing Sarcoma (EwS) is a highly aggressive tumor of bone and soft tissues that mostly affects children and adolescents. The pathognomonic oncofusion EWSR1-ETS (EWSR1-FLI1/EWSR1-ERG) transcription factors drive EwS by orchestrating an oncogenic transcription program through de novo enhancers. Pharmacological targeting of these oncofusions has been challenged by unstructured prion-like domains and common DNA binding domains in the EWSR1 and ETS protein, respectively. Alternatively, identification and characterization of mediators and downstream targets of EWSR1-FLI1 dependent or independent function could offer novel therapeutic options. By integrative analysis of thousands of transcriptome datasets representing pan-cancer cell lines, primary cancer, metastasis, and normal tissues, we have identified a 32 gene signature (ESS32 - Ewing Sarcoma Specific 32) that could stratify EwS from pan-cancer. Of the ESS32, LOXHD1 - that encodes a stereociliary protein, was the most exquisitely expressed gene in EwS. CRISPR-Cas9 mediated deletion or silencing of EWSR1-FLI1 bound upstream de novo enhancer elements in EwS cells led to the loss of LOXHD1 expression and altered the EWSR1-FLI1, MYC, and HIF1 pathway genes, resulting in decreased proliferation and invasion in vitro and in vivo. These observations implicate LOXHD1 as a novel biomarker and a major determinant of EwS metastasis and open up new avenues for developing LOXHD1-targeted drugs or cellular therapies for this deadly disease.

cancer biology↗

bioRxiv2020

Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19

Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and TMPRSS2 by androgen in mouse and human cells. Additionally, we demonstrate the endogenous interaction between TMPRSS2 and ACE2 in human cells and validate ACE2 as a TMPRSS2 substrate. Further, Camostat - a TMPRSS2 inhibitor, blocked the cleavage of pseudotype SARS-CoV-2 surface Spike without disrupting TMPRSS2-ACE2 interaction. Thus providing evidence for the first time a direct role of TMPRSS2 in priming the SARS-CoV-2 Spike, required for viral fusion to the host cell. Importantly, androgen-deprivation, anti-androgens, or Camostat attenuated the SARS-CoV-2 S-mediated cellular entry. Together, our data provide a strong rationale for clinical evaluations of TMPRSS2 inhibitors, androgen-deprivation therapy/androgen receptor antagonists alone or in combination with antiviral drugs as early as clinically possible to prevent COVID-19 progression.

molecular biology↗